Advertisement

Hepatic, Extra-hepatic Outcomes and Causes of Mortality in NAFLD. An Umbrella Overview of Systematic Review of Meta-Analysis

  • Author Footnotes
    $ These two authors contributed equally to this work and share first authorship
    Jieling Xiao
    Footnotes
    $ These two authors contributed equally to this work and share first authorship
    Affiliations
    MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
    Search for articles by this author
  • Author Footnotes
    $ These two authors contributed equally to this work and share first authorship
    Cheng Han Ng
    Correspondence
    Corresponding author. Ng Cheng Han, Yong Loo Lin School of Medicine, National University of SingaporeSingapore 10 Medical Dr, Singapore 117597 Tel: +65 6772 3737,
    Footnotes
    $ These two authors contributed equally to this work and share first authorship
    Affiliations
    MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
    Search for articles by this author
  • Kai En Chan
    Affiliations
    MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
    Search for articles by this author
  • Clarissa Fu
    Affiliations
    MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
    Search for articles by this author
  • Phoebe Tay
    Affiliations
    MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
    Search for articles by this author
  • Jie Ning Yong
    Affiliations
    MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
    Search for articles by this author
  • Wen Hui Lim
    Affiliations
    MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
    Search for articles by this author
  • Darren Jun Hao Tan
    Affiliations
    MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
    Search for articles by this author
  • Nicholas Syn
    Affiliations
    MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
    Search for articles by this author
  • Zhen Yu Wong
    Affiliations
    School of Medicine, International Medical University, Kuala Lumpur, Malaysia
    Search for articles by this author
  • Michael Tseng
    Affiliations
    Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia
    Search for articles by this author
  • Nicholas Chew
    Affiliations
    Department of Cardiology, National University Heart Centre, National University Hospital, Singapore
    Search for articles by this author
  • Daniel Q. Huang
    Affiliations
    MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore

    Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore

    National University Centre for Organ Transplantation, National University Health System, Singapore
    Search for articles by this author
  • Yock Young Dan
    Affiliations
    MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore

    Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore

    National University Centre for Organ Transplantation, National University Health System, Singapore
    Search for articles by this author
  • Vincent Wai-Sun Wong
    Affiliations
    Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
    Search for articles by this author
  • Rohit Loomba
    Affiliations
    NAFLD Research Centre, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, San Diego, California, USA
    Search for articles by this author
  • Mohammad Shadab Siddiqui
    Affiliations
    Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia
    Search for articles by this author
  • Arun J. Sanyal
    Affiliations
    Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia
    Search for articles by this author
  • Author Footnotes
    # Equal Supervision
    Mazen Noureddin
    Footnotes
    # Equal Supervision
    Affiliations
    Houston Research Institute, Houston Liver Institute, Houston, Texas, USA
    Search for articles by this author
  • Author Footnotes
    # Equal Supervision
    Mark D. Muthiah
    Correspondence
    Corresponding author. Dr. Mark Muthiah, MBBS (S’pore), MRCP (UK), MMED (S’pore), Consultant Gastroenterologist and Hepatologist, Division of Gastroenterology and Hepatology, Tower Block Level 10, 1E Kent Ridge Road Singapore 119228 Tel: +65 6772 4354 Fax: +65 6775 1518,
    Footnotes
    # Equal Supervision
    Affiliations
    MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore

    Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore

    National University Centre for Organ Transplantation, National University Health System, Singapore
    Search for articles by this author
  • Author Footnotes
    $ These two authors contributed equally to this work and share first authorship
    # Equal Supervision
Published:November 18, 2022DOI:https://doi.org/10.1016/j.jceh.2022.11.006

      Abstract

      Background

      Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease globally. While the prevalence, impact and causes of mortality has been described in various meta-analysis, a systematic all-encompassing umbrella review has yet to 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 was 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, subclinical and clinical coronary heart disease were also significantly elevated in NAFLD individuals compared to individuals without NAFLD. Additionally, NAFLD was associated with increased risk of all-cause (HR: 1.34, CI: 1.17 to 1.54), 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.

      Keywords

      Abbreviations:

      NAFLD (Non-alcoholic fatty liver disease), VLDLs (Very-low-density lipoproteins), CVD (Cardiovascular disease), HCC (Hepatocellular carcinoma), CKD (Chronic kidney disease), FLI (Fatty liver index), CAP (Controlled attenuation parameter), CT (Computed tomography), MRI (Magnetic resonance imaging), BMI (Body-mass index), T2DM (Type 2 diabetes mellitus), IR (Insulin resistance)

      Introduction

      Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease affecting 25-33% of the global population.
      • Muthiah M.D.
      • Sanyal A.J.
      Burden of Disease due to Nonalcoholic Fatty Liver Disease.
      ,
      • Lim G.E.H.
      • Tang A.
      • Ng C.H.
      • et al.
      An Observational Data Meta-analysis on the Differences in Prevalence and Risk Factors Between MAFLD vs NAFLD.
      Accompanying a growing metabolic disease epidemic, the prevalence of NAFLD has been rising consistently, in addition, it is closely associated with the presence of obesity and diabetes.
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      ,
      • Bril F.
      • Cusi K.
      Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Call to Action.
      While there are multiple factors involved in the causation of NAFLD, the pathophysiology of NAFLD involves the inability of the liver to handle lipids and excrete very-low-density lipoproteins (VLDLs), causing hepatocellular injury and hepatic fibrosis as the disease progresses.
      • Parthasarathy G.
      • Revelo X.
      • Malhi H.
      Pathogenesis of Nonalcoholic Steatohepatitis: An Overview.
      • Loomba R.
      • Friedman S.L.
      • Shulman G.I.
      Mechanisms and disease consequences of nonalcoholic fatty liver disease.
      • Softic S.
      • Cohen D.E.
      • Kahn C.R.
      Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease.
      • Ter Horst K.W.
      • Serlie M.J.
      Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease.
      • Loomba R.
      • Quehenberger O.
      • Armando A.
      • Dennis E.A.
      Polyunsaturated fatty acid metabolites as novel lipidomic biomarkers for noninvasive diagnosis of nonalcoholic steatohepatitis.
      • Ng C.H.
      • Muthiah M.D.
      • Xiao J.
      • et al.
      Meta-analysis: analysis of mechanistic pathways in the treatment of non-alcoholic steatohepatitis. Evidence from a Bayesian network meta-analysis.
      Furthermore, links between NAFLD and multiple hepatic and extrahepatic complications has been established
      • Ng C.H.
      • Huang D.Q.
      • Nguyen M.H.
      NAFLD versus MAFLD: Prevalence, Outcomes and Implications of a Change in Name.
      • Chew N.W.S.
      • Ng C.H.
      • Muthiah M.D.
      • Sanyal A.J.
      Comprehensive Review and Updates on Holistic Approach Towards Non-Alcoholic Fatty Liver Disease Management with Cardiovascular Disease.
      • Ng C.H.
      • Chan K.E.
      • Chin Y.H.
      • et al.
      The Effect of Diabetes and Prediabetes on the Prevalence, Complications and Mortality in Non-alcoholic Fatty Liver Disease.
      • Yong J.N.
      • Ng C.H.
      • Lee C.W.
      • et al.
      Non-alcoholic fatty liver disease association with structural heart, systolic and diastolic dysfunction: a meta-analysis.
      • Tang A.S.P.
      • Chan K.E.
      • Quek J.
      • et al.
      NAFLD increases Risk of Carotid Atherosclerosis and Ischemic Stroke. An Updated Meta-Analysis with 135,602 Individuals.
      . The presence of NAFLD has been associated with an increased risk in cardiovascular disease (CVD), stroke, hepatocellular carcinoma (HCC), and chronic kidney disease (CKD) along with other systemic diseases. NAFLD is also currently the fastest growing cause of HCC with up to 40% of patients presenting without cirrhosis.
      • Tan D.J.H.
      • Ng C.H.
      • Lin S.Y.
      • et al.
      Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis.
      ,
      • Noureddin M.
      • Rinella M.E.
      Nonalcoholic Fatty liver disease, diabetes, obesity, and hepatocellular carcinoma.
      Similarly, NAFLD has become a major contributor of indications for liver transplantation and is associated with an increase in CVD related events post-LT compared to patients without the disease.

      Yong JN, Lim WH, Ng CH, et al. Outcomes of Nonalcoholic Steatohepatitis After Liver Transplantation: An Updated Meta-Analysis and Systematic Review. Clin Gastroenterol Hepatol. Nov 18 2021;doi:10.1016/j.cgh.2021.11.014

      ,
      • Noureddin M.
      • Vipani A.
      • Bresee C.
      • et al.
      NASH Leading Cause of Liver Transplant in Women: Updated Analysis of Indications For Liver Transplant and Ethnic and Gender Variances.
      However, despite the significant burden of NAFLD, global awareness of NAFLD remains considerably low. A recent study conducted on the global preparedness of NAFLD found that policies and strategies for the prevention and management of NAFLD has been persistently lacking.
      • Lazarus J.V.
      • Mark H.E.
      • Anstee Q.M.
      • et al.
      Advancing the global public health agenda for NAFLD: a consensus statement.
      • Lazarus J.V.
      • Palayew A.
      • Carrieri P.
      • et al.
      European ‘NAFLD Preparedness Index’ — Is Europe ready to meet the challenge of fatty liver disease?.
      • Byrne C.D.
      • Newsome P.N.
      • Noureddin M.
      Why are there no strategies for NAFLD?.
      The significant burden and rising interest of NAFLD has in turn given rise to a myriad of meta-analyses summarizing the prevalence and associated end organ complications of NAFLD compared to non-NAFLD patients. Meta-analysis remains the highest order of clinical evidence providing pooled events based on existing literature but the certainty of evidence remains unclear, in part due to risk of bias, scheme design defects, publication bias, or inconsistencies in overlapping meta-analyses
      • Bergstrom J.C.
      • Taylor L.O.
      Using meta-analysis for benefits transfer: Theory and practice.
      . This presents a major challenge in literature interpretation and to date, there has yet to be a systematic effort to summarize and critically appraise the evidence. Umbrella reviews not only provide a means for a prompt review of broad and high-quality evidence regarding the topic of discussion, but also allows for a better recognition of the uncertainties, biases, and knowledge gaps.
      • Ioannidis J.
      Next-generation systematic reviews: prospective meta-analysis, individual-level data, networks and umbrella reviews.
      Given the notable burden of NAFLD, an umbrella review could aid in improving interpretability of established evidence in a reliable manner, thereby potentially guiding developments in clinical management and improving global awareness of NAFLD. Thus, we sought to conduct an updated umbrella systematic review of existing meta-analyses on the associated complications and causes of mortality of NAFLD.

      Methods

      Search Strategy

      This umbrella review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      ,
      • Hutton B.
      • Salanti G.
      • Caldwell D.M.
      • et al.
      The PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions: Checklist and Explanations.
      . A comprehensive search was conducted on Medline and Embase electronic databases with assistance from a medical librarian for meta-analyses on the prevalence and outcomes of NAFLD. The search was conducted from inception on 1 March 2022 and used search terms including “NAFLD”, “meta-analysis” and “systematic review”. The full search strategy can be found in supplementary material 1. All references were imported into Endnote X9 for removal of duplicates. To ensure a comprehensive search, the bibliographies of the included articles were also screened.

      Eligibility Criteria and Data extraction

      Four authors (JX, CHN, KEC, CF) independently conducted the screening of abstracts and evaluation of full text for inclusion. Discrepancies were then resolved through consensus and consultation with a senior author (MDM). The eligibility criteria for this umbrella review are (i) meta-analyses of articles with observational study designs (e.g., cohort study, case-control study, or cross-sectional study), (ii) articles that investigated the associated complications of NAFLD and/or (iii) investigated the causes of mortality in NAFLD patients with relation to non-NAFLD individuals. Review articles without quantitative analysis and studies including animal trials or in vitro investigations were excluded. In this umbrella review, only English articles were included. The focus of this review was primarily on the adult population and pediatric studies were excluded. Four authors (JX, CHN, KEC, CF) independently extracted data from each included meta-analysis which includes author, publication year, journal name, number of studies included, study population and outcome(s) of interest investigated.
      The unit of measurement along with the effect sizes including risk ratio (RR), odds ratio (OR), hazard ratio (HR), mean difference (MD), weighted mean difference (WMD), incidence rate (IR) and 95% confidence intervals (95% CI), and heterogeneity measures (I2 values) were extracted. There was no conversion of units between effect sizes to maintain nature of the unit of analysis. When there are overlapping meta-analyses published on similar outcomes of interest, the higher quality study will be preferred as an inclusion over later studies. The quality of the study can be judge by the unit of analysis or a higher score in the Assessment of Multiple Systematic Reviews 2 (AMSTAR-2). HR is preferred to account for longitudinal risk
      • Spruance S.L.
      • Reid J.E.
      • Grace M.
      • Samore M.
      Hazard Ratio in Clinical Trials.
      whereas OR offers ease of interpretation, however, can exaggerate the size of effect compared to risk ratio and does not account for longitudinal risk
      • Davies H.T.O.
      • Crombie I.K.
      • Tavakoli M.
      When can odds ratios mislead?.
      . Random effects model was also preferred over the fixed effect model since it better accounts for between study heterogeneity that often prevalent in observational studies

      Deeks JJ HJ, Altman DG (editors). Chapter 10: Analysing data and undertaking meta-analyses. Cochrane Handbook for Systematic Reviews of Interventions version 63. updated February 2022

      . Discrepancies between the data extracted were resolved by a fifth investigator (MDM).

      Results Synthesis and Quality Assessment

      For each eligible meta-analysis, the summary effect size and the corresponding 95% confidence intervals (CI) were extracted. Re-analysis including but not limited to pooling of the effect size was not performed to prevent overlapping of primary articles and to maintain the original nature of the analysis. Similarly, unit of analysis within the articles did not undergo conversion of events and the summary effect sizes were presented as RR, OR, HR, MD, WMD, IR and corresponding 95% CI. The corresponding effect sizes were extracted and was summarized in a forest plot. Statistical heterogeneity was assessed via I2 values where an I2 value of ≥40% was considered heterogeneous.
      • Fletcher J.
      What is heterogeneity and is it important?.
      ,
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      The methodological quality of the included meta-analyses was evaluated using the AMSTAR-2 checklist, a popular instrument for assessing systematic reviews of randomized and non-randomized studies.
      • Shea B.J.
      • Reeves B.C.
      • Wells G.
      • et al.
      AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both.
      The AMSTAR-2 checklist consists of 16 items which assess the quality of meta-analyses, including seven critical domains which are registration of protocol prior to commencement of study, adequacy of literature search, sufficient explanation provided for exclusion of studies, risk of bias of individual studies, suitability of statistical methodology used, consideration for risk of bias in interpretation of results and evaluation of publication bias.
      • Shea B.J.
      • Reeves B.C.
      • Wells G.
      • et al.
      AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both.
      AMSTAR-2 then rates the quality of meta-analyses as high, moderate, low and critically low based on presence of non-critical or critical weakness.
      • Shea B.J.
      • Reeves B.C.
      • Wells G.
      • et al.
      AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both.

      Results

      Summary of Included Articles

      From the initial search strategy, 2734 references were retrieved with 2483 remaining after duplicate removal. After screening of title and abstract, 91 full texts were reviewed (Figure 1). A total of 25 meta-analyses were then included in this umbrella review (supplementary material 2). There were 25 meta-analyses reported data on the complications of NAFLD with 3 studies utilizing MD
      • Yong J.N.
      • Ng C.H.
      • Lee C.W.
      • et al.
      Non-alcoholic fatty liver disease association with structural heart, systolic and diastolic dysfunction: a meta-analysis.
      ,
      • Fan Y.
      • Wei F.
      • Zhou Y.
      • Zhang H.
      Association of non-alcoholic fatty liver disease with impaired endothelial function by flow-mediated dilation: A meta-analysis.
      ,
      • Jaruvongvanich V.
      • Chenbhanich J.
      • Sanguankeo A.
      • Rattanawong P.
      • Wijarnpreecha K.
      • Upala S.
      Increased arterial stiffness in nonalcoholic fatty liver disease: a systematic review and meta-analysis.
      , 13 studies utilizing OR
      • Tang A.S.P.
      • Chan K.E.
      • Quek J.
      • et al.
      NAFLD increases Risk of Carotid Atherosclerosis and Ischemic Stroke. An Updated Meta-Analysis with 135,602 Individuals.
      ,
      • Jaruvongvanich V.
      • Sanguankeo A.
      • Upala S.
      Significant Association Between Gallstone Disease and Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.
      • Corrao S.
      • Natoli G.
      • Argano C.
      Nonalcoholic fatty liver disease is associated with intrahepatic cholangiocarcinoma and not with extrahepatic form: definitive evidence from meta-analysis and trial sequential analysis.
      • Gong H.
      • Liu X.
      • Cheng F.
      Relationship between non-alcoholic fatty liver disease and cardiac arrhythmia: a systematic review and meta-analysis.
      • Toh J.Z.K.
      • Pan X.H.
      • Tay P.W.L.
      • et al.
      A Meta-Analysis on the Global Prevalence, Risk factors and Screening of Coronary Heart Disease in Nonalcoholic Fatty Liver Disease.
      • Jullian-Desayes I.
      • Trzepizur W.
      • Boursier J.
      • et al.
      Obstructive sleep apnea, chronic obstructive pulmonary disease and NAFLD: an individual participant data meta-analysis.
      • Greco C.
      • Nascimbeni F.
      • Carubbi F.
      • Andreone P.
      • Simoni M.
      • Santi D.
      Association of Nonalcoholic Fatty Liver Disease (NAFLD) with Peripheral Diabetic Polyneuropathy: A Systematic Review and Meta-Analysis.
      • Qin S.
      • Wang S.
      • Wang X.
      • Wang J.
      Non-alcoholic fatty liver disease and the risk of urolithiasis: A systematic review and meta-analysis.
      • Wijarnpreecha K.
      • Thongprayoon C.
      • Boonpheng B.
      • et al.
      Nonalcoholic fatty liver disease and albuminuria: a systematic review and meta-analysis.
      • Xiao J.
      • Lim L.K.E.
      • Ng C.H.
      • et al.
      Is Fatty Liver Associated With Depression? A Meta-Analysis and Systematic Review on the Prevalence, Risk Factors, and Outcomes of Depression and Non-alcoholic Fatty Liver Disease.
      • Xue J.
      • Xin H.
      • Ren N.
      • et al.
      Nonalcoholic fatty liver disease increases the risk of gastroesophageal reflux disease: A systematic review and meta-analysis.
      • Mantovani A.
      • Dauriz M.
      • Gatti D.
      • et al.
      Systematic review with meta-analysis: non-alcoholic fatty liver disease is associated with a history of osteoporotic fractures but not with low bone mineral density.
      • Mantovani A.
      • Petracca G.
      • Csermely A.
      • et al.
      Non-alcoholic fatty liver disease and risk of new-onset heart failure: an updated meta-analysis of about 11 million individuals.
      , 2 studies utilizing WMD
      • Mantovani A.
      • Dauriz M.
      • Gatti D.
      • et al.
      Systematic review with meta-analysis: non-alcoholic fatty liver disease is associated with a history of osteoporotic fractures but not with low bone mineral density.
      ,
      • Mantovani A.
      • Lonardo A.
      • Vinco G.
      • et al.
      Association between non-alcoholic fatty liver disease and decreased lung function in adults: A systematic review and meta-analysis.
      , 6 studies using HR
      • Mantovani A.
      • Csermely A.
      • Petracca G.
      • et al.
      Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis.
      • Ciardullo S.
      • Grassi G.
      • Mancia G.
      • Perseghin G.
      Nonalcoholic fatty liver disease and risk of incident hypertension: a systematic review and meta-analysis.
      • Mantovani A.
      • Petracca G.
      • Beatrice G.
      • et al.
      Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies.
      • Mantovani A.
      • Petracca G.
      • Beatrice G.
      • Tilg H.
      • Byrne C.D.
      • Targher G.
      Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals.
      • Liu Y.
      • Zhong G.-C.
      • Tan H.-Y.
      • Hao F.-B.
      • Hu J.-J.
      Nonalcoholic fatty liver disease and mortality from all causes, cardiovascular disease, and cancer: a meta-analysis.
      • Mantovani A.
      • Petracca G.
      • Beatrice G.
      • et al.
      Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis.
      and one study each utilizing RR
      • Cai X.
      • Zheng S.
      • Liu Y.
      • Zhang Y.
      • Lu J.
      • Huang Y.
      Nonalcoholic fatty liver disease is associated with increased risk of atrial fibrillation.
      and IR
      • Orci L.A.
      • Sanduzzi-Zamparelli M.
      • Caballol B.
      • et al.
      Incidence of Hepatocellular Carcinoma in Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review, Meta-analysis, and Meta-regression.
      as units of measurement. A summary of the included studies can be found in supplementary material 2. Majority of the included meta-analyses were found to have low or moderate risk of bias (supplementary material 3) and the original risk of bias assessment presented in the included articles can be found in supplementary material 4.

      Complications of NAFLD

      Hepatic Complications

      There were three included studies reporting hepatic complications associated with NAFLD. The incidence rate of hepatocellular carcinoma in NAFLD was 2.39 per 100 person years (CI: 1.40 to 4.08, n = 470,404, I2 = 93.0%) as reported in a study by Orci et al
      • Orci L.A.
      • Sanduzzi-Zamparelli M.
      • Caballol B.
      • et al.
      Incidence of Hepatocellular Carcinoma in Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review, Meta-analysis, and Meta-regression.
      . According to a study done by Carrao et al, individuals with NAFLD are also associated with increased cholangiocarcinoma (n = 68,694, OR: 1.88, CI: 1.25 to 2.83, I2 = 79.7%) compared to individuals without NAFLD
      • Corrao S.
      • Natoli G.
      • Argano C.
      Nonalcoholic fatty liver disease is associated with intrahepatic cholangiocarcinoma and not with extrahepatic form: definitive evidence from meta-analysis and trial sequential analysis.
      . NAFLD was also associated with an increase in gallstone disease (n = 79,629, OR: 1.55, CI: 1.31 to 1.82, I2 = 64.0%) in comparison with patients without NAFLD according to a study done by Jaruvongvanich et al (Figure 2)
      • Jaruvongvanich V.
      • Sanguankeo A.
      • Upala S.
      Significant Association Between Gallstone Disease and Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.
      .
      Figure 2
      Figure 2Summary Forest plot of Hepatic complications. Legend: 100PY, 100 person years; OR, Odds ratio; 95% CI, 95% Confidence Interval.

      Cardiovascular Disease (CVD)

      Nine of the included articles assessed cardiovascular related complications in NAFLD. In an analysis of 5,790,329 individuals by Mantovani et al, NAFLD was associated with a higher risk of fatal and non-fatal CVD events (HR: 1.45, CI: 1.31 to 1.61, I2 = 86.2%) compared to non-NAFLD individuals
      • Mantovani A.
      • Csermely A.
      • Petracca G.
      • et al.
      Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis.
      . There was a 40% increase in non-fatal CVD events in NAFLD compared to non-NAFLD individuals (n = 5,240,595, HR: 1.40, CI: 1.20 to 1.64, I2 = 87.7%)
      • Mantovani A.
      • Csermely A.
      • Petracca G.
      • et al.
      Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis.
      . Coronary heart disease (CHD), Subclinical and clinical coronary heart disease were significantly elevated in NAFLD individuals (Figure 3) compared to individuals without NAFLD as reported by Toh et al
      • Toh J.Z.K.
      • Pan X.H.
      • Tay P.W.L.
      • et al.
      A Meta-Analysis on the Global Prevalence, Risk factors and Screening of Coronary Heart Disease in Nonalcoholic Fatty Liver Disease.
      . In a study by Mantovani et al, NAFLD was associated with increased risk of new onset heart failure compared to individuals without NALFD (n = 11,242,231, OR: 1.50, CI: 1.34 to 1.67, I2 = 94.8%)
      • Mantovani A.
      • Petracca G.
      • Csermely A.
      • et al.
      Non-alcoholic fatty liver disease and risk of new-onset heart failure: an updated meta-analysis of about 11 million individuals.
      . An analysis of 23,793 individuals found that there was a significant increase in carotid atherosclerosis (OR: 3.20, CI: 2.37 to 4.32, I2 = 87.8%) and stroke events (n = 83,043, OR: 1.88, CI: 1.23 to 2.88, I2 = 45.3%), particularly for ischemic stroke (n = 82,146, OR: 2.05, CI: 1.05 to 1.98, I2 = 57.3%) in individuals with NAFLD compared to those without in a study done by Tang et al
      • Tang A.S.P.
      • Chan K.E.
      • Quek J.
      • et al.
      NAFLD increases Risk of Carotid Atherosclerosis and Ischemic Stroke. An Updated Meta-Analysis with 135,602 Individuals.
      . In comparison to individuals without NAFLD, individuals with NAFLD were also associated with an increase in atrial fibrillation, prolong QT Interval, premature ventricular contractions, and heart blocks as reported by Cai et al
      • Cai X.
      • Zheng S.
      • Liu Y.
      • Zhang Y.
      • Lu J.
      • Huang Y.
      Nonalcoholic fatty liver disease is associated with increased risk of atrial fibrillation.
      and Gong et al
      • Gong H.
      • Liu X.
      • Cheng F.
      Relationship between non-alcoholic fatty liver disease and cardiac arrhythmia: a systematic review and meta-analysis.
      (Figure 3). In a study by Ciardullo et al, elevated risk for hypertension was similarly observed in NAFLD individuals (n = 390,348, HR: 1.66, CI: 1.38 to 2.01, I2 = 90.9%) than in individuals without NAFLD
      • Ciardullo S.
      • Grassi G.
      • Mancia G.
      • Perseghin G.
      Nonalcoholic fatty liver disease and risk of incident hypertension: a systematic review and meta-analysis.
      .
      Figure 3
      Figure 3Summary Forest plot of cardiovascular diseases. Legend: CVD, Cardiovascular; PVC/PAC; Premature Ventricular Contractions/Premature Atrial Contractions; CAD, Coronary Artery Disease; HR, Hazard ratio; MD, Mean difference; OR, Odds ratio; RR, Risk ratio; 95% CI, 95% Confidence Interval.

      Systemic Malignancies

      NAFLD was associated with the highest risk of thyroid cancers (n = 64,732, HR: 2.63, CI: 1.27 to 5.45, I2 = 0.0%) compared to individuals without NAFLD amongst all the systemic malignancy related to NAFLD. Significantly, GI related cancers including esophageal, pancreatic, stomach, colorectal were significantly elevated in individuals with NAFLD compared to individuals without NAFLD (Figure 5). Compared to individuals without NAFLD, NAFLD was also associated with an increase in colorectal adenomas (n = 14,244, HR: 1.40, CI: 1.20 to 1.63, I2 = 30.0%). Other cancers including but not limited to lung, urinary system, breast, gynecological and prostate were also significantly elevated in individuals with NAFLD than in individuals without NAFLD (Figure 4). Result estimates of systemic malignancies associated with NAFLD were reported in one study by Mantovani et al
      • Mantovani A.
      • Petracca G.
      • Beatrice G.
      • et al.
      Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies.
      .
      Figure 5
      Figure 5Summary Forest plot of other complications associated with NAFLD and Summary Forest plot of other clinical and biometric measurements. Legend: COPD, Chronic Obstructive Pulmonary Disease; OSA, Obstructive Sleep Apnea; GERD, Gastroesophageal Reflux Disease; BMD, Bone mineral density; LVEF, left ventricle ejection fraction; E, peak E wave; A, peak A wave; LVM, left ventricular mass; LVEDD, left ventricle end-diastolic diameter; LVESD, left ventricle end-systolic diameter; LAD, left atrial diameter; PWT, posterior wall; EAT, epicardial adipose thickness; HR, Hazard ratio; 95% CI, 95% Confidence Interval; OR, Odds ratio; WMD, Weighted mean difference; MD, Mean difference.
      Figure 4
      Figure 4Summary Forest plot of Systemic malignancies. Legend: HR, Hazard ratio; 95% CI, 95% Confidence Interval.

      Other Complications and Associated Measurements

      Eight studies reported other complications while three studies presented other clinical and biometric measurements. The presence of NAFLD was associated with an increased risk of diabetes than in individuals without NAFLD in an analysis of 501,022 patients (HR: 2.19, CI: 1.93 to 2.48, I2 = 91.2%) by Mantovani et al
      • Mantovani A.
      • Petracca G.
      • Beatrice G.
      • Tilg H.
      • Byrne C.D.
      • Targher G.
      Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals.
      . Similarly, NAFLD significantly increases the risk of chronic kidney disease (n = 1,215,872, HR: 1.43, CI: 1.33 to 1.54, I2 = 60.7%) compared to individuals without NAFLD as reported by Mantovani et al
      • Mantovani A.
      • Petracca G.
      • Beatrice G.
      • et al.
      Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis.
      . NAFLD was also related with an increased risk of frailty associated with osteoporosis (n = 10,492, OR: 1.43, CI: 1.00 to 2.06, I2 = 55.1%) compared to non-NAFLD in a study by Mantovani et al
      • Mantovani A.
      • Dauriz M.
      • Gatti D.
      • et al.
      Systematic review with meta-analysis: non-alcoholic fatty liver disease is associated with a history of osteoporotic fractures but not with low bone mineral density.
      . Other associated risk of NAFLD and clinical measurements are summarized in Figure 5.

      Cause of Mortality

      Causes of mortality in NAFLD patients was reported in two included studies. The presence of NAFLD was associated with an increased risk of all-cause mortality (HR: 1.34, CI: 1.17 to 1.54, I2 = 80.0%) but not in cancer related mortality (n= 465,112, HR 1.05, CI: 0.89 to 1.25, I2 = 35.3%) in comparison to the absence of NAFLD in a study by Liu et al
      • Liu Y.
      • Zhong G.-C.
      • Tan H.-Y.
      • Hao F.-B.
      • Hu J.-J.
      Nonalcoholic fatty liver disease and mortality from all causes, cardiovascular disease, and cancer: a meta-analysis.
      . As reported by Mantovani et al, NAFLD was also associated with increased risk of CVD related mortality (n = 414,333, HR, 1.30, CI: 1.08 to 1.56, I2 = 86.1%, figure 6)
      • Mantovani A.
      • Csermely A.
      • Petracca G.
      • et al.
      Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis.
      .
      Figure 6
      Figure 6Cause of mortality in patients with NAFLD. Legend: CVD, Cardiovascular; HR, Hazard ratio; 95% CI, 95% Confidence Interval.

      Discusssion

      Given the rapidly rising rates of NAFLD, the current umbrella review provides a comprehensive update of the literature on the associated outcomes and causes of mortality in NAFLD based on the highest quality evidence from existing meta-analyses. The prevalence of NAFLD will only continue to increase in parallel with the metabolic disease epidemic given the lack of effective pharmacological treatment for the disease.
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      ,
      • Bril F.
      • Cusi K.
      Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Call to Action.
      In turn, consolidating the evidence with an umbrella review provides informative results on the whole hosts of systemic complications associated with NAFLD which raises public awareness of the significant burden of the disease. This serves to underscore the urgent need for effective measures and multidisciplinary care models to address the incoming NAFLD crisis.
      Importantly, NAFLD was associated with a host of extrahepatic and hepatic complications particularly that of CVD.
      • Chew N.W.S.
      • Ng C.H.
      • Muthiah M.D.
      • Sanyal A.J.
      Comprehensive Review and Updates on Holistic Approach Towards Non-Alcoholic Fatty Liver Disease Management with Cardiovascular Disease.
      ,
      • Yong J.N.
      • Ng C.H.
      • Lee C.W.
      • et al.
      Non-alcoholic fatty liver disease association with structural heart, systolic and diastolic dysfunction: a meta-analysis.
      ,
      • Tang A.S.P.
      • Chan K.E.
      • Quek J.
      • et al.
      NAFLD increases Risk of Carotid Atherosclerosis and Ischemic Stroke. An Updated Meta-Analysis with 135,602 Individuals.
      The link between NAFLD and CVD is well-established in existing literature given that NAFLD is closely related to many traditional CVD risk factors including but not limited to metabolic syndrome, hypertension and dyslipidemia.
      • Adams L.A.
      • Anstee Q.M.
      • Tilg H.
      • Targher G.
      Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases.
      • Angulo P.
      • Lindor K.D.
      Non-alcoholic fatty liver disease.
      • Marchesini G.
      • Bugianesi E.
      • Forlani G.
      • et al.
      Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome.
      • Kasper P.
      • Martin A.
      • Lang S.
      • et al.
      NAFLD and cardiovascular diseases: a clinical review.
      The increase in systemic malignancies in NAFLD may also be the result of alterations in metabolic and stress-response mechanisms caused by NAFLD or the accompanying byproduct of metabolic dysregulation, obesity and/or hormonal derangements.
      • Allen A.M.
      • Hicks S.B.
      • Mara K.C.
      • Larson J.J.
      • Therneau T.M.
      The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity - A longitudinal cohort study.
      • Kyrgiou M.
      • Kalliala I.
      • Markozannes G.
      • et al.
      Adiposity and cancer at major anatomical sites: umbrella review of the literature.
      • Kim G.-A.
      • Lee H.C.
      • Choe J.
      • et al.
      Association between non-alcoholic fatty liver disease and cancer incidence rate.
      • Michelotti G.A.
      • Machado M.V.
      • Diehl A.M.
      NAFLD, NASH and liver cancer.
      Existing literature also suggest that NAFLD facilitates a microenvironment suitable for carcinogenesis due to insulin resistance and chronic inflammation.
      • Kim G.-A.
      • Lee H.C.
      • Choe J.
      • et al.
      Association between non-alcoholic fatty liver disease and cancer incidence rate.
      ,
      • Sanna C.
      • Rosso C.
      • Marietti M.
      • Bugianesi E.
      Non-Alcoholic Fatty Liver Disease and Extra-Hepatic Cancers.
      ,
      • Gilbert C.A.
      • Slingerland J.M.
      Cytokines, Obesity, and Cancer: New Insights on Mechanisms Linking Obesity to Cancer Risk and Progression.
      Furthermore, NAFLD was associated with significant hepatic complications including hepatocellular carcinoma, cholangiocarcinoma and gallstone diseases as illustrated in the present review. It is widely recognized that NAFLD contributes significantly to increased risk for HCC due to accumulation of lipids in hepatocytes which drives carcinogenesis through oxidative DNA damage.
      • Loomba R.
      • Friedman S.L.
      • Shulman G.I.
      Mechanisms and disease consequences of nonalcoholic fatty liver disease.
      ,
      • Orci L.A.
      • Sanduzzi-Zamparelli M.
      • Caballol B.
      • et al.
      Incidence of Hepatocellular Carcinoma in Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review, Meta-analysis, and Meta-regression.
      ,
      • Kanwal F.
      • Kramer J.R.
      • Mapakshi S.
      • et al.
      Risk of Hepatocellular Cancer in Patients With Non-Alcoholic Fatty Liver Disease.
      While screening and surveillance for HCC in patients with non-alcoholic steatohepatitis (NASH) is recommended by the American Association for the Study of Liver Diseases, it has only been recommended in the context of cirrhosis.
      • Marrero J.A.
      • Kulik L.M.
      • Sirlin C.B.
      • et al.
      Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases.
      However, a recent meta-analysis by Tan and Ng et al found that up to a third of HCC in NAFLD occur in non-cirrhotic patients.
      • Tan D.J.H.
      • Ng C.H.
      • Lin S.Y.
      • et al.
      Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis.
      However, while there is an increased risk of HCC in NAFLD, The absolute risk may be not be sufficiently high enough to justify routine screening given the significant prevalence of NAFLD and low cost screening methods are required to identify patients at risk for HCC evaluation. In addition, NAFLD was also found to be associated with increased risk of cholangiocarcinoma, especially hepatic cholangiocarcinoma. This might be attributed to NAFLD induced systemic inflammation, resulting in hyperinsulinemia and increased insulin-like growth factor-1 which stimulates cell proliferation in cholangiocarcinoma.
      • Corrao S.
      • Natoli G.
      • Argano C.
      Nonalcoholic fatty liver disease is associated with intrahepatic cholangiocarcinoma and not with extrahepatic form: definitive evidence from meta-analysis and trial sequential analysis.
      Lastly, the pathogenesis of increased gallstone disease in patients with NAFLD could be related to the multiple common risk factors shared such as increased age, BMI, diabetes and hypertension.
      • Jaruvongvanich V.
      • Sanguankeo A.
      • Upala S.
      Significant Association Between Gallstone Disease and Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.
      ,
      • Konyn P.
      • Alshuwaykh O.
      • Dennis B.B.
      • Cholankeril G.
      • Ahmed A.
      • Kim D.
      Gallstone Disease and Its Association With Nonalcoholic Fatty Liver Disease, All-Cause and Cause-Specific Mortality.
      With the rapidly growing prevalence and global burden of NAFLD evident in its wide hosts of associated extrahepatic disease, there is an urgent need to refocus public health efforts to target the development of multidisciplinary care models. Studies have positioned the establishment of a multilevel intervention involving stakeholders ranging from researchers, healthcare providers to policy makers and funders as a vital need to address the NAFLD epidemic.
      • Lazarus J.V.
      • Mark H.E.
      • Anstee Q.M.
      • et al.
      Advancing the global public health agenda for NAFLD: a consensus statement.
      Additionally, the awareness of the disease remains low in the community with recent reviews highlighting that relevant knowledge of NAFLD is generally poor in non-hepatologists and efforts should also gear towards increasing cognizance and awareness surrounding fatty liver amongst general practitioners, patients, and relatives of patients.
      • Lazarus J.V.
      • Mark H.E.
      • Anstee Q.M.
      • et al.
      Advancing the global public health agenda for NAFLD: a consensus statement.
      ,
      • Bergqvist C.J.
      • Skoien R.
      • Horsfall L.
      • Clouston A.D.
      • Jonsson J.R.
      • Powell E.E.
      Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists.

      Strengths and limitations

      This umbrella review systematically and comprehensively presented evidence on the associated complications and causes of mortality in patients with NAFLD through consolidated information from various meta-analyses. The current review encompasses a thorough evaluation of clinically relevant information on NAFLD based on various meta-analyses, which were assessed for methodological quality and robustness of evidence. However, there are several limitations. We were limited to the studies that have been thoroughly examined in previous meta-analyses and complications that have yet to be examined may have been excluded in the selection process. There was additionally moderate to high statistical heterogeneity in most of the outcomes presented by the included meta-analyses. Furthermore, there could be a potential overlap in included studies across the various meta-analyses reviewed. There is also currently a lack of published literature evaluating potential differences in various outcomes measures based on region or demographic factors, which can be a focus for future studies. Lastly, the diagnosis of NAFLD may be limited by the primary articles where ICD-9/10 coding may also be employed for large scale population-based analysis.

      Conclusions

      In this umbrella review, data from published meta-analyses were assessed to evaluate and update the complications and causes of mortality in patients with NAFLD. In particularly, NAFLD was associated with significant hepatic complications, cardiovascular diseases, systemic malignancies, and metabolic complications. A multi-faceted intervention should be adopted to tackle the disease burden of NAFLD.

      Declarations

      Registration and protocol

      Study was not registered.

      Funding

      No funding was required for this study.

      Conflicts of Interests

      Arun J. Sanyal: Dr Sanyal is President of Sanyal Biotechnology and has stock options in Genfit, Akarna, Tiziana, Indalo, Durect and Galmed. He has served as a consultant to Astra Zeneca, Nitto Denko, Enyo, Ardelyx, Conatus, Nimbus, Amarin, Salix, Tobira, Takeda, Jannsen, Gilead, Terns, Birdrock, Merck, Valeant, Boehringer-Ingelheim, Lilly, Hemoshear, Zafgen, Novartis, Novo Nordisk, Pfizer, Exhalenz and Genfit. He has been an unpaid consultant to Intercept, Echosens, Immuron, Galectin, Fractyl, Syntlogic, Affimune, Chemomab, Zydus, Nordic Bioscience, Albireo, Prosciento, Surrozen and Bristol Myers Squibb. His institution has received grant support from Gilead, Salix, Tobira, Bristol Myers, Shire, Intercept, Merck, Astra Zeneca, Malinckrodt, Cumberland and Norvatis. He receives royalties from Elsevier and UptoDate.
      Mazen Noureddin: Dr Noureddin MN has been on the advisory board/consultant for 89BIO, Altimmune, Gilead, cohBar, Cytodyn, Intercept, Pfizer, Novo Nordisk, Blade, EchoSens, Fractyl, Madrgial, NorthSea, Prespecturm, Terns, Siemens and Roche diagnostic; MN has received research support from Allergan, BMS, Gilead, Galmed, Galectin, Genfit, Conatus, Enanta, Madrigal, Novartis, Pfizer, Shire, Viking and Zydus; MN is a shareholder or has stocks in Anaetos, Chrownwell, Ciema, Rivus Pharma and Viking.
      Vincent Wong: Dr Wong has served as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Merck, Novo Nordisk, Pfizer, ProSciento, Sagimet Biosciences, and TARGET PharmaSolutions; and a speaker for Abbott, AbbVie, Echosens, Gilead Sciences, and Novo Nordisk. He has received a research grant from Gilead Sciences and is a cofounder of Illuminatio Medical Technology Limited.
      Rohit Loomba: Dr. Loomba consults and received grants from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Galmed, Gilead, Intercept, Janssen, Madrigal, NGM, and Pfizer. He consults for Anylam/Regeneron, Amgen, Arrowhead, CohBar, Glympse, Inipharm, Ionis, Metacrine, Novartis, Novo Nordisk, Sagimet, 89 Bio, and Viking. He received grants from Allergan, Boehringer Ingelheim, Galectin, Genfit, Inventiva, Merck, and Siemens.
      All other authors have no conflicts of interests.

      Data Availability

      All articles in this manuscript are available from Medline and Embase.

      Author Contributions

      Conception and design: Cheng-Han Ng, Mark D. Muthiah
      Administrative support: Nicholas Syn, Zhen Yu Wong, Michael Tseng, Nicholas Chew, Daniel Q Huang, Yock Young Dan, Vincent Wai-Sun Wong, Mohammad Shadab Siddiqui, Arun J. Sanyal, Rohit Loomba, Mazen Noureddin, Mark D. Muthiah
      Provision of study materials or patients: Nicholas Syn, Zhen Yu Wong, Michael Tseng, Nicholas Chew, Daniel Q Huang, Yock Young Dan, Vincent Wai-Sun Wong, Mohammad Shadab Siddiqui, Arun J. Sanyal, Rohit Loomba, Mazen Noureddin, Mark D. Muthiah
      Collection and assembly of data: Jieling Xiao, Cheng Han Ng, Kai En Chan, Clarissa Fu, Phoebe Tay, Jie Ning Yong, Wen Hui Lim, Darren Jun Hao Tan
      Data analysis and interpretation: Jieling Xiao, Cheng Han Ng, Kai En Chan, Clarissa Fu, Phoebe Tay, Jie Ning Yong, Wen Hui Lim, Darren Jun Hao Tan
      Manuscript writing: All authors
      Final Approval of manuscript: All authors

      Acknowledgements

      All authors have made substantial contributions to all of the following: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted. No writing assistance was obtained in the preparation of the manuscript. The manuscript, including related data, figures and tables has not been previously published and that the manuscript is not under consideration elsewhere.

      References

        • Muthiah M.D.
        • Sanyal A.J.
        Burden of Disease due to Nonalcoholic Fatty Liver Disease.
        Gastroenterol Clin North Am. Mar. 2020; 49: 1-23https://doi.org/10.1016/j.gtc.2019.09.007
        • Lim G.E.H.
        • Tang A.
        • Ng C.H.
        • et al.
        An Observational Data Meta-analysis on the Differences in Prevalence and Risk Factors Between MAFLD vs NAFLD.
        Clin Gastroenterol Hepatol. Dec 4 2021; https://doi.org/10.1016/j.cgh.2021.11.038
        • Younossi Z.M.
        • Koenig A.B.
        • Abdelatif D.
        • Fazel Y.
        • Henry L.
        • Wymer M.
        Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
        Hepatology. Jul 2016; 64: 73-84https://doi.org/10.1002/hep.28431
        • Bril F.
        • Cusi K.
        Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Call to Action.
        Diabetes care. 2017; 40: 419-430https://doi.org/10.2337/dc16-1787
        • Parthasarathy G.
        • Revelo X.
        • Malhi H.
        Pathogenesis of Nonalcoholic Steatohepatitis: An Overview.
        Hepatology Communications. 2020; 4 (2020/04/01, doi:https://doi.org/10.1002/hep4.1479): 478-492https://doi.org/10.1002/hep4.1479
        • Loomba R.
        • Friedman S.L.
        • Shulman G.I.
        Mechanisms and disease consequences of nonalcoholic fatty liver disease.
        Cell. 2021/05/13/ 2021; 184: 2537-2564https://doi.org/10.1016/j.cell.2021.04.015
        • Softic S.
        • Cohen D.E.
        • Kahn C.R.
        Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease.
        Dig Dis Sci. May. 2016; 61: 1282-1293https://doi.org/10.1007/s10620-016-4054-0
        • Ter Horst K.W.
        • Serlie M.J.
        Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease.
        Nutrients. Sep 6. 2017; 9https://doi.org/10.3390/nu9090981
        • Loomba R.
        • Quehenberger O.
        • Armando A.
        • Dennis E.A.
        Polyunsaturated fatty acid metabolites as novel lipidomic biomarkers for noninvasive diagnosis of nonalcoholic steatohepatitis.
        J Lipid Res. Jan. 2015; 56: 185-192https://doi.org/10.1194/jlr.P055640
        • Ng C.H.
        • Muthiah M.D.
        • Xiao J.
        • et al.
        Meta-analysis: analysis of mechanistic pathways in the treatment of non-alcoholic steatohepatitis. Evidence from a Bayesian network meta-analysis.
        Aliment Pharmacol Ther. May 2022; 55: 1076-1087https://doi.org/10.1111/apt.16808
        • Ng C.H.
        • Huang D.Q.
        • Nguyen M.H.
        NAFLD versus MAFLD: Prevalence, Outcomes and Implications of a Change in Name.
        Clin Mol Hepatol. May 11 2022; https://doi.org/10.3350/cmh.2022.0070
        • Chew N.W.S.
        • Ng C.H.
        • Muthiah M.D.
        • Sanyal A.J.
        Comprehensive Review and Updates on Holistic Approach Towards Non-Alcoholic Fatty Liver Disease Management with Cardiovascular Disease.
        Curr Atheroscler Rep. May 4 2022; https://doi.org/10.1007/s11883-022-01027-5
        • Ng C.H.
        • Chan K.E.
        • Chin Y.H.
        • et al.
        The Effect of Diabetes and Prediabetes on the Prevalence, Complications and Mortality in Non-alcoholic Fatty Liver Disease.
        Clin Mol Hepatol. May 19 2022; https://doi.org/10.3350/cmh.2022.0096
        • Yong J.N.
        • Ng C.H.
        • Lee C.W.
        • et al.
        Non-alcoholic fatty liver disease association with structural heart, systolic and diastolic dysfunction: a meta-analysis.
        Hepatol Int. Apr. 2022; 16: 269-281https://doi.org/10.1007/s12072-022-10319-6
        • Tang A.S.P.
        • Chan K.E.
        • Quek J.
        • et al.
        NAFLD increases Risk of Carotid Atherosclerosis and Ischemic Stroke. An Updated Meta-Analysis with 135,602 Individuals.
        Clin Mol Hepatol. Mar. 2022; : 2https://doi.org/10.3350/cmh.2021.0406
        • Tan D.J.H.
        • Ng C.H.
        • Lin S.Y.
        • et al.
        Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis.
        The Lancet Oncology. 2022; 23: 521-530https://doi.org/10.1016/S1470-2045(22)00078-X
        • Noureddin M.
        • Rinella M.E.
        Nonalcoholic Fatty liver disease, diabetes, obesity, and hepatocellular carcinoma.
        Clin Liver Dis. May. 2015; 19: 361-379https://doi.org/10.1016/j.cld.2015.01.012
      1. Yong JN, Lim WH, Ng CH, et al. Outcomes of Nonalcoholic Steatohepatitis After Liver Transplantation: An Updated Meta-Analysis and Systematic Review. Clin Gastroenterol Hepatol. Nov 18 2021;doi:10.1016/j.cgh.2021.11.014

        • Noureddin M.
        • Vipani A.
        • Bresee C.
        • et al.
        NASH Leading Cause of Liver Transplant in Women: Updated Analysis of Indications For Liver Transplant and Ethnic and Gender Variances.
        Am J Gastroenterol. Nov. 2018; 113: 1649-1659https://doi.org/10.1038/s41395-018-0088-6
        • Lazarus J.V.
        • Mark H.E.
        • Anstee Q.M.
        • et al.
        Advancing the global public health agenda for NAFLD: a consensus statement.
        Nature Reviews Gastroenterology & Hepatology. 2022/01/01 2022; 19: 60-78https://doi.org/10.1038/s41575-021-00523-4
        • Lazarus J.V.
        • Palayew A.
        • Carrieri P.
        • et al.
        European ‘NAFLD Preparedness Index’ — Is Europe ready to meet the challenge of fatty liver disease?.
        JHEP Reports. 2021; 3https://doi.org/10.1016/j.jhepr.2021.100234
        • Byrne C.D.
        • Newsome P.N.
        • Noureddin M.
        Why are there no strategies for NAFLD?.
        J Hepatol. Apr. 2022; 76: 763-764https://doi.org/10.1016/j.jhep.2021.12.009
        • Bergstrom J.C.
        • Taylor L.O.
        Using meta-analysis for benefits transfer: Theory and practice.
        Ecological Economics. 2006/12/01/ 2006; 60: 351-360https://doi.org/10.1016/j.ecolecon.2006.06.015
        • Ioannidis J.
        Next-generation systematic reviews: prospective meta-analysis, individual-level data, networks and umbrella reviews.
        Br J Sports Med. Oct. 2017; 51: 1456-1458https://doi.org/10.1136/bjsports-2017-097621
        • Page M.J.
        • McKenzie J.E.
        • Bossuyt P.M.
        • et al.
        The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
        BMJ. 2021; 372: n71https://doi.org/10.1136/bmj.n71
        • Hutton B.
        • Salanti G.
        • Caldwell D.M.
        • et al.
        The PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions: Checklist and Explanations.
        Annals of Internal Medicine. 2015/06/02 2015; 162: 777-784https://doi.org/10.7326/M14-2385
        • Spruance S.L.
        • Reid J.E.
        • Grace M.
        • Samore M.
        Hazard Ratio in Clinical Trials.
        Antimicrobial Agents and Chemotherapy. 2004; 48: 2787-2792https://doi.org/10.1128/AAC.48.8.2787-2792.2004
        • Davies H.T.O.
        • Crombie I.K.
        • Tavakoli M.
        When can odds ratios mislead?.
        BMJ. 1998; 316: 989https://doi.org/10.1136/bmj.316.7136.989
      2. Deeks JJ HJ, Altman DG (editors). Chapter 10: Analysing data and undertaking meta-analyses. Cochrane Handbook for Systematic Reviews of Interventions version 63. updated February 2022

        • Fletcher J.
        What is heterogeneity and is it important?.
        BMJ (Clinical research ed). 2007; 334: 94-96https://doi.org/10.1136/bmj.39057.406644.68
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188https://doi.org/10.1016/0197-2456(86)90046-2
        • Shea B.J.
        • Reeves B.C.
        • Wells G.
        • et al.
        AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both.
        BMJ. 2017; 358: j4008https://doi.org/10.1136/bmj.j4008
        • Fan Y.
        • Wei F.
        • Zhou Y.
        • Zhang H.
        Association of non-alcoholic fatty liver disease with impaired endothelial function by flow-mediated dilation: A meta-analysis.
        Hepatol Res. Mar. 2016; 46: E165-E173https://doi.org/10.1111/hepr.12554
        • Jaruvongvanich V.
        • Chenbhanich J.
        • Sanguankeo A.
        • Rattanawong P.
        • Wijarnpreecha K.
        • Upala S.
        Increased arterial stiffness in nonalcoholic fatty liver disease: a systematic review and meta-analysis.
        Eur J Gastroenterol Hepatol. Sep. 2017; 29: e28-e35https://doi.org/10.1097/meg.0000000000000909
        • Jaruvongvanich V.
        • Sanguankeo A.
        • Upala S.
        Significant Association Between Gallstone Disease and Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.
        Dig Dis Sci. Aug. 2016; 61: 2389-2396https://doi.org/10.1007/s10620-016-4125-2
        • Corrao S.
        • Natoli G.
        • Argano C.
        Nonalcoholic fatty liver disease is associated with intrahepatic cholangiocarcinoma and not with extrahepatic form: definitive evidence from meta-analysis and trial sequential analysis.
        Eur J Gastroenterol Hepatol. Jan. 2021; 33: 62-68https://doi.org/10.1097/meg.0000000000001684
        • Gong H.
        • Liu X.
        • Cheng F.
        Relationship between non-alcoholic fatty liver disease and cardiac arrhythmia: a systematic review and meta-analysis.
        J Int Med Res. Sep. 2021; 493000605211047074https://doi.org/10.1177/03000605211047074
        • Toh J.Z.K.
        • Pan X.H.
        • Tay P.W.L.
        • et al.
        A Meta-Analysis on the Global Prevalence, Risk factors and Screening of Coronary Heart Disease in Nonalcoholic Fatty Liver Disease.
        Clin Gastroenterol Hepatol. Sep 22 2021; https://doi.org/10.1016/j.cgh.2021.09.021
        • Jullian-Desayes I.
        • Trzepizur W.
        • Boursier J.
        • et al.
        Obstructive sleep apnea, chronic obstructive pulmonary disease and NAFLD: an individual participant data meta-analysis.
        Sleep Med. Jan. 2021; 77: 357-364https://doi.org/10.1016/j.sleep.2020.04.004
        • Greco C.
        • Nascimbeni F.
        • Carubbi F.
        • Andreone P.
        • Simoni M.
        • Santi D.
        Association of Nonalcoholic Fatty Liver Disease (NAFLD) with Peripheral Diabetic Polyneuropathy: A Systematic Review and Meta-Analysis.
        J Clin Med. Sep. 2021; 28: 10https://doi.org/10.3390/jcm10194466
        • Qin S.
        • Wang S.
        • Wang X.
        • Wang J.
        Non-alcoholic fatty liver disease and the risk of urolithiasis: A systematic review and meta-analysis.
        Medicine (Baltimore). Aug 2018; 97e12092https://doi.org/10.1097/md.0000000000012092
        • Wijarnpreecha K.
        • Thongprayoon C.
        • Boonpheng B.
        • et al.
        Nonalcoholic fatty liver disease and albuminuria: a systematic review and meta-analysis.
        Eur J Gastroenterol Hepatol. Sep. 2018; 30: 986-994https://doi.org/10.1097/meg.0000000000001169
        • Xiao J.
        • Lim L.K.E.
        • Ng C.H.
        • et al.
        Is Fatty Liver Associated With Depression? A Meta-Analysis and Systematic Review on the Prevalence, Risk Factors, and Outcomes of Depression and Non-alcoholic Fatty Liver Disease.
        Front Med (Lausanne). 2021; 8691696
        • Xue J.
        • Xin H.
        • Ren N.
        • et al.
        Nonalcoholic fatty liver disease increases the risk of gastroesophageal reflux disease: A systematic review and meta-analysis.
        Eur J Clin Invest. Sep. 2019; 49e13158https://doi.org/10.1111/eci.13158
        • Mantovani A.
        • Dauriz M.
        • Gatti D.
        • et al.
        Systematic review with meta-analysis: non-alcoholic fatty liver disease is associated with a history of osteoporotic fractures but not with low bone mineral density.
        Aliment Pharmacol Ther. Feb. 2019; 49: 375-388https://doi.org/10.1111/apt.15087
        • Mantovani A.
        • Petracca G.
        • Csermely A.
        • et al.
        Non-alcoholic fatty liver disease and risk of new-onset heart failure: an updated meta-analysis of about 11 million individuals.
        Gut. 2022; (gutjnl-2022-327672)https://doi.org/10.1136/gutjnl-2022-327672
        • Mantovani A.
        • Lonardo A.
        • Vinco G.
        • et al.
        Association between non-alcoholic fatty liver disease and decreased lung function in adults: A systematic review and meta-analysis.
        Diabetes Metab. Dec. 2019; 45: 536-544https://doi.org/10.1016/j.diabet.2019.04.008
        • Mantovani A.
        • Csermely A.
        • Petracca G.
        • et al.
        Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis.
        Lancet Gastroenterol Hepatol. Nov. 2021; 6: 903-913https://doi.org/10.1016/s2468-1253(21)00308-3
        • Ciardullo S.
        • Grassi G.
        • Mancia G.
        • Perseghin G.
        Nonalcoholic fatty liver disease and risk of incident hypertension: a systematic review and meta-analysis.
        Eur J Gastroenterol Hepatol. Apr 1 2022; 34: 365-371https://doi.org/10.1097/meg.0000000000002299
        • Mantovani A.
        • Petracca G.
        • Beatrice G.
        • et al.
        Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies.
        Gut. Apr. 2022; 71: 778-788https://doi.org/10.1136/gutjnl-2021-324191
        • Mantovani A.
        • Petracca G.
        • Beatrice G.
        • Tilg H.
        • Byrne C.D.
        • Targher G.
        Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals.
        Gut. May 2021; 70: 962-969https://doi.org/10.1136/gutjnl-2020-322572
        • Liu Y.
        • Zhong G.-C.
        • Tan H.-Y.
        • Hao F.-B.
        • Hu J.-J.
        Nonalcoholic fatty liver disease and mortality from all causes, cardiovascular disease, and cancer: a meta-analysis.
        Scientific Reports. 2019/07/31 2019; 911124https://doi.org/10.1038/s41598-019-47687-3
        • Mantovani A.
        • Petracca G.
        • Beatrice G.
        • et al.
        Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis.
        Gut. Jan. 2022; 71: 156-162https://doi.org/10.1136/gutjnl-2020-323082
        • Cai X.
        • Zheng S.
        • Liu Y.
        • Zhang Y.
        • Lu J.
        • Huang Y.
        Nonalcoholic fatty liver disease is associated with increased risk of atrial fibrillation.
        Liver Int. Jul. 2020; 40: 1594-1600https://doi.org/10.1111/liv.14461
        • Orci L.A.
        • Sanduzzi-Zamparelli M.
        • Caballol B.
        • et al.
        Incidence of Hepatocellular Carcinoma in Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review, Meta-analysis, and Meta-regression.
        Clin Gastroenterol Hepatol. Feb. 2022; 20 (e10): 283-292https://doi.org/10.1016/j.cgh.2021.05.002
        • Adams L.A.
        • Anstee Q.M.
        • Tilg H.
        • Targher G.
        Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases.
        Gut. 2017; 66: 1138https://doi.org/10.1136/gutjnl-2017-313884
        • Angulo P.
        • Lindor K.D.
        Non-alcoholic fatty liver disease.
        Journal of gastroenterology and hepatology. 2002; 17: S186-S190
        • Marchesini G.
        • Bugianesi E.
        • Forlani G.
        • et al.
        Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome.
        Hepatology. Apr. 2003; 37: 917-923https://doi.org/10.1053/jhep.2003.50161
        • Kasper P.
        • Martin A.
        • Lang S.
        • et al.
        NAFLD and cardiovascular diseases: a clinical review.
        Clin Res Cardiol. Jul. 2021; 110: 921-937https://doi.org/10.1007/s00392-020-01709-7
        • Allen A.M.
        • Hicks S.B.
        • Mara K.C.
        • Larson J.J.
        • Therneau T.M.
        The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity - A longitudinal cohort study.
        J Hepatol. Dec. 2019; 71: 1229-1236https://doi.org/10.1016/j.jhep.2019.08.018
        • Kyrgiou M.
        • Kalliala I.
        • Markozannes G.
        • et al.
        Adiposity and cancer at major anatomical sites: umbrella review of the literature.
        BMJ. 2017; 356: j477https://doi.org/10.1136/bmj.j477
        • Kim G.-A.
        • Lee H.C.
        • Choe J.
        • et al.
        Association between non-alcoholic fatty liver disease and cancer incidence rate.
        Journal of Hepatology. 2018/01/01/ 2018; 68: 140-146https://doi.org/10.1016/j.jhep.2017.09.012
        • Michelotti G.A.
        • Machado M.V.
        • Diehl A.M.
        NAFLD, NASH and liver cancer.
        Nat Rev Gastroenterol Hepatol. Nov. 2013; 10: 656-665https://doi.org/10.1038/nrgastro.2013.183
        • Sanna C.
        • Rosso C.
        • Marietti M.
        • Bugianesi E.
        Non-Alcoholic Fatty Liver Disease and Extra-Hepatic Cancers.
        International Journal of Molecular Sciences. 2016; 17https://doi.org/10.3390/ijms17050717
        • Gilbert C.A.
        • Slingerland J.M.
        Cytokines, Obesity, and Cancer: New Insights on Mechanisms Linking Obesity to Cancer Risk and Progression.
        Annual Review of Medicine. 2013/01/14 2013; 64: 45-57https://doi.org/10.1146/annurev-med-121211-091527
        • Kanwal F.
        • Kramer J.R.
        • Mapakshi S.
        • et al.
        Risk of Hepatocellular Cancer in Patients With Non-Alcoholic Fatty Liver Disease.
        Gastroenterology. Dec 2018; 155: 1828-1837https://doi.org/10.1053/j.gastro.2018.08.024
        • Marrero J.A.
        • Kulik L.M.
        • Sirlin C.B.
        • et al.
        Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases.
        Hepatology. Aug. 2018; 68: 723-750https://doi.org/10.1002/hep.29913
        • Konyn P.
        • Alshuwaykh O.
        • Dennis B.B.
        • Cholankeril G.
        • Ahmed A.
        • Kim D.
        Gallstone Disease and Its Association With Nonalcoholic Fatty Liver Disease, All-Cause and Cause-Specific Mortality.
        Clinical Gastroenterology and Hepatology. 2022/05/26/ 2022; https://doi.org/10.1016/j.cgh.2022.04.043
        • Bergqvist C.J.
        • Skoien R.
        • Horsfall L.
        • Clouston A.D.
        • Jonsson J.R.
        • Powell E.E.
        Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists.
        Intern Med J. Mar. 2013; 43: 247-253https://doi.org/10.1111/j.1445-5994.2012.02848.x