{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:46:27Z","timestamp":1791600387083,"version":"4.3.4"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,8,16]],"date-time":"2025-08-16T00:00:00Z","timestamp":1755302400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,8,16]],"date-time":"2025-08-16T00:00:00Z","timestamp":1755302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"Shaoxing Municipal Health Science and Technology Plan Project","award":["2023SKY086"],"award-info":[{"award-number":["2023SKY086"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Discov Onc"],"DOI":"10.1007\/s12672-025-03350-0","type":"journal-article","created":{"date-parts":[[2025,8,16]],"date-time":"2025-08-16T07:56:24Z","timestamp":1755330984000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Bidirectional Mendelian randomization analysis and systematic meta-analysis of causal relationships between hepatocellular carcinoma and non-alcoholic fatty liver disease"],"prefix":"10.1007","volume":"16","author":[{"given":"Tielong","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanglieguang","family":"Lou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,16]]},"reference":[{"issue":"3","key":"3350_CR1","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/j.cgh.2021.11.038","volume":"21","author":"GEH Lim","year":"2023","unstructured":"Lim GEH, et al. An observational data Meta-analysis on the differences in prevalence and risk factors between MAFLD vs NAFLD. Clin Gastroenterol Hepatol. 2023;21(3):619\u2013e6297.","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"1","key":"3350_CR2","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/hep.28431","volume":"64","author":"ZM Younossi","year":"2016","unstructured":"Younossi ZM, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73\u201384.","journal-title":"Hepatology"},{"issue":"1","key":"3350_CR3","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1002\/hep.29466","volume":"67","author":"C Estes","year":"2018","unstructured":"Estes C, et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67(1):123\u201333.","journal-title":"Hepatology"},{"issue":"9","key":"3350_CR4","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.1111\/apt.16808","volume":"55","author":"CH Ng","year":"2022","unstructured":"Ng CH, 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. 2022;55(9):1076\u201387.","journal-title":"Aliment Pharmacol Ther"},{"issue":"1","key":"3350_CR5","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1111\/liv.14355","volume":"40","author":"MD Muthiah","year":"2020","unstructured":"Muthiah MD, Sanyal AJ. Current management of non-alcoholic steatohepatitis. Liver Int. 2020;40(1):89\u201395.","journal-title":"Liver Int"},{"issue":"Suppl 2","key":"3350_CR6","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/dom.14521","volume":"24","author":"MD Muthiah","year":"2022","unstructured":"Muthiah MD, Han NC, Sanyal AJ. A clinical overview of non-alcoholic fatty liver disease: A guide to diagnosis, the clinical features, and complications-What the non-specialist needs to know. Diabetes Obes Metab. 2022;24(Suppl 2):3\u201314.","journal-title":"Diabetes Obes Metab"},{"key":"3350_CR7","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1146\/annurev-pathol-020117-043617","volume":"13","author":"JP Arab","year":"2018","unstructured":"Arab JP, Arrese M, Trauner M. Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev Pathol. 2018;13:321\u201350.","journal-title":"Annu Rev Pathol"},{"issue":"1","key":"3350_CR8","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1002\/hep.28906","volume":"65","author":"G Garcia-Tsao","year":"2017","unstructured":"Garcia-Tsao G, et al. Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American association for the study of liver diseases. Hepatology. 2017;65(1):310\u201335.","journal-title":"Hepatology"},{"issue":"5","key":"3350_CR9","doi-asserted-by":"publisher","first-page":"962","DOI":"10.1136\/gutjnl-2020-322572","volume":"70","author":"A Mantovani","year":"2021","unstructured":"Mantovani A, et al. Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals. Gut. 2021;70(5):962\u20139.","journal-title":"Gut"},{"issue":"10","key":"3350_CR10","doi-asserted-by":"publisher","first-page":"3017","DOI":"10.1007\/s10620-013-2743-5","volume":"58","author":"M Stepanova","year":"2013","unstructured":"Stepanova M, et al. Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci. 2013;58(10):3017\u201323.","journal-title":"Dig Dis Sci"},{"issue":"9","key":"3350_CR11","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1136\/gutjnl-2020-320622","volume":"69","author":"G Targher","year":"2020","unstructured":"Targher G, Byrne CD, Tilg H. NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and Pharmacological implications. Gut. 2020;69(9):1691\u2013705.","journal-title":"Gut"},{"issue":"3","key":"3350_CR12","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/j.jhep.2016.05.013","volume":"65","author":"G Targher","year":"2016","unstructured":"Targher G, et al. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J Hepatol. 2016;65(3):589\u2013600.","journal-title":"J Hepatol"},{"issue":"4","key":"3350_CR13","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1136\/gutjnl-2021-324191","volume":"71","author":"A Mantovani","year":"2022","unstructured":"Mantovani A, et al. Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies. Gut. 2022;71(4):778\u201388.","journal-title":"Gut"},{"issue":"7","key":"3350_CR14","doi-asserted-by":"publisher","first-page":"e1001680","DOI":"10.1371\/journal.pmed.1001680","volume":"11","author":"G Musso","year":"2014","unstructured":"Musso G, et al. Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med. 2014;11(7):e1001680.","journal-title":"PLoS Med"},{"key":"3350_CR15","doi-asserted-by":"crossref","unstructured":"Tanase DM et al. The intricate relationship between type 2 diabetes mellitus (T2DM), insulin resistance (IR), and nonalcoholic fatty liver disease (NAFLD). J Diabetes Res, 2020;2020:3920196.","DOI":"10.1155\/2020\/3920196"},{"issue":"4","key":"3350_CR16","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1016\/j.cgh.2022.04.014","volume":"21","author":"CH Ng","year":"2023","unstructured":"Ng CH, et al. Mortality outcomes by fibrosis stage in nonalcoholic fatty liver disease: A systematic review and Meta-analysis. Clin Gastroenterol Hepatol. 2023;21(4):931\u2013e9395.","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"1","key":"3350_CR17","doi-asserted-by":"publisher","first-page":"11124","DOI":"10.1038\/s41598-019-47687-3","volume":"9","author":"Y Liu","year":"2019","unstructured":"Liu Y, et al. Nonalcoholic fatty liver disease and mortality from all causes, cardiovascular disease, and cancer: a meta-analysis. Sci Rep. 2019;9(1):11124.","journal-title":"Sci Rep"},{"key":"3350_CR18","doi-asserted-by":"publisher","first-page":"33386","DOI":"10.1038\/srep33386","volume":"6","author":"S Wu","year":"2016","unstructured":"Wu S, et al. Association of non-alcoholic fatty liver disease with major adverse cardiovascular events: A systematic review and meta-analysis. Sci Rep. 2016;6:33386.","journal-title":"Sci Rep"},{"issue":"8","key":"3350_CR19","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1111\/apt.15673","volume":"51","author":"C Estes","year":"2020","unstructured":"Estes C, et al. Modelling NAFLD disease burden in four Asian regions-2019-2030. Aliment Pharmacol Ther. 2020;51(8):801\u201311.","journal-title":"Aliment Pharmacol Ther"},{"key":"3350_CR20","doi-asserted-by":"publisher","first-page":"n71","DOI":"10.1136\/bmj.n71","volume":"372","author":"MJ Page","year":"2021","unstructured":"Page MJ, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.","journal-title":"BMJ"},{"issue":"15","key":"3350_CR21","doi-asserted-by":"publisher","first-page":"2008","DOI":"10.1001\/jama.283.15.2008","volume":"283","author":"DF Stroup","year":"2000","unstructured":"Stroup DF, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA. 2000;283(15):2008\u201312.","journal-title":"JAMA"},{"issue":"8","key":"3350_CR22","first-page":"MR000026","volume":"2011","author":"T Horsley","year":"2011","unstructured":"Horsley T, Dingwall O, Sampson M. Checking reference lists to find additional studies for systematic reviews. Cochrane Database Syst Rev. 2011;2011(8):MR000026.","journal-title":"Cochrane Database Syst Rev"},{"key":"3350_CR23","doi-asserted-by":"publisher","first-page":"d6891","DOI":"10.1136\/bmj.d6891","volume":"343","author":"M Lazo","year":"2011","unstructured":"Lazo M, et al. Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study. BMJ. 2011;343:d6891.","journal-title":"BMJ"},{"issue":"7414","key":"3350_CR24","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1136\/bmj.327.7414.557","volume":"327","author":"JP Higgins","year":"2003","unstructured":"Higgins JP, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557\u201360.","journal-title":"BMJ"},{"issue":"2","key":"3350_CR25","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1002\/hep.31040","volume":"72","author":"CS Alvarez","year":"2020","unstructured":"Alvarez CS, et al. Attributable fractions of nonalcoholic fatty liver disease for mortality in the united states: results from the third National health and nutrition examination survey with 27 years of Follow-up. Hepatology. 2020;72(2):430\u201340.","journal-title":"Hepatology"},{"issue":"5","key":"3350_CR26","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.1002\/hep.27368","volume":"61","author":"M Ekstedt","year":"2015","unstructured":"Ekstedt M, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61(5):1547\u201354.","journal-title":"Hepatology"},{"issue":"7","key":"3350_CR27","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1016\/j.cgh.2017.11.026","volume":"16","author":"YC Hwang","year":"2018","unstructured":"Hwang YC, et al. Nonalcoholic fatty liver disease associates with increased overall mortality and death from cancer, cardiovascular disease, and liver disease in women but not men. Clin Gastroenterol Hepatol. 2018;16(7):1131\u2013e11375.","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"2","key":"3350_CR28","doi-asserted-by":"publisher","first-page":"341","DOI":"10.2337\/dc17-1590","volume":"41","author":"SH Wild","year":"2018","unstructured":"Wild SH, et al. Cardiovascular disease, cancer, and mortality among people with type 2 diabetes and alcoholic or nonalcoholic fatty liver disease hospital admission. Diabetes Care. 2018;41(2):341\u20137.","journal-title":"Diabetes Care"},{"issue":"10","key":"3350_CR29","doi-asserted-by":"publisher","first-page":"e0241357","DOI":"10.1371\/journal.pone.0241357","volume":"15","author":"JP Mann","year":"2020","unstructured":"Mann JP, et al. Hospital admission with non-alcoholic fatty liver disease is associated with increased all-cause mortality independent of cardiovascular risk factors. PLoS ONE. 2020;15(10):e0241357.","journal-title":"PLoS ONE"},{"issue":"7","key":"3350_CR30","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1136\/gutjnl-2020-322786","volume":"70","author":"TG Simon","year":"2021","unstructured":"Simon TG, et al. Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort. Gut. 2021;70(7):1375\u201382.","journal-title":"Gut"},{"issue":"3","key":"3350_CR31","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1111\/liv.15171","volume":"42","author":"O Nabi","year":"2022","unstructured":"Nabi O, et al. The burden of NAFLD in type 2 diabetic subjects from the general population: A nationwide population-based follow-up study (NASHCO). Liver Int. 2022;42(3):595\u2013606.","journal-title":"Liver Int"},{"key":"3350_CR32","unstructured":"Kim GA et al. Association between non-alcoholic fatty liver disease and cancer incidence rate. J Hepatol. 2017; (17)32294-8."},{"issue":"10319","key":"3350_CR33","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/S0140-6736(21)01701-3","volume":"399","author":"TH Karlsen","year":"2022","unstructured":"Karlsen TH, et al. The EASL-Lancet liver commission: protecting the next generation of Europeans against liver disease complications and premature mortality. Lancet. 2022;399(10319):61\u2013116.","journal-title":"Lancet"},{"issue":"7","key":"3350_CR34","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1007\/s11883-022-01027-5","volume":"24","author":"NWS Chew","year":"2022","unstructured":"Chew NWS, et al. Comprehensive review and updates on holistic approach towards Non-Alcoholic fatty liver disease management with cardiovascular disease. Curr Atheroscler Rep. 2022;24(7):515\u201332.","journal-title":"Curr Atheroscler Rep"},{"issue":"4","key":"3350_CR35","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/S1470-2045(22)00078-X","volume":"23","author":"DJH Tan","year":"2022","unstructured":"Tan DJH, et al. Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis. Lancet Oncol. 2022;23(4):521\u201330.","journal-title":"Lancet Oncol"},{"issue":"2","key":"3350_CR36","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.cgh.2021.05.002","volume":"20","author":"LA Orci","year":"2022","unstructured":"Orci LA, et al. Incidence of hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: A systematic review, Meta-analysis, and Meta-regression. Clin Gastroenterol Hepatol. 2022;20(2):283\u2013e29210.","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"3","key":"3350_CR37","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1111\/liv.13031","volume":"36","author":"C Margini","year":"2016","unstructured":"Margini C, Dufour JF. The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment. Liver Int. 2016;36(3):317\u201324.","journal-title":"Liver Int"},{"issue":"16","key":"3350_CR38","doi-asserted-by":"publisher","first-page":"715","DOI":"10.4254\/wjh.v9.i16.715","volume":"9","author":"M Benedict","year":"2017","unstructured":"Benedict M, Zhang X. Non-alcoholic fatty liver disease: an expanded review. World J Hepatol. 2017;9(16):715\u201332.","journal-title":"World J Hepatol"},{"key":"3350_CR39","doi-asserted-by":"crossref","unstructured":"Baumgartner S, Shiri-Sverdlov R. NASH and systemic complications: from basic to clinical research. Biomedicines, 2021;9(12):1913.","DOI":"10.3390\/biomedicines9121913"},{"issue":"1","key":"3350_CR40","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1186\/s12876-022-02290-1","volume":"22","author":"A Sugiyama","year":"2022","unstructured":"Sugiyama A, et al. Distribution of FIB-4 index in the general population: analysis of 75,666 residents who underwent health checkups. BMC Gastroenterol. 2022;22(1):241.","journal-title":"BMC Gastroenterol"}],"container-title":["Discover Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-025-03350-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12672-025-03350-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-025-03350-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T14:54:09Z","timestamp":1757429649000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12672-025-03350-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,16]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["3350"],"URL":"https:\/\/doi.org\/10.1007\/s12672-025-03350-0","relation":{},"ISSN":["2730-6011"],"issn-type":[{"value":"2730-6011","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,16]]},"assertion":[{"value":"8 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not available.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The Author confirms: that its publication has been approved by all co-authors.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1564"}}