{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:50:20Z","timestamp":1791388220167,"version":"4.3.3"},"reference-count":47,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,4,15]],"date-time":"2022-04-15T00:00:00Z","timestamp":1649980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["771083"],"award-info":[{"award-number":["771083"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"German Cancer Aid","doi-asserted-by":"publisher","award":["110043"],"award-info":[{"award-number":["110043"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB-TRR57\/P06"],"award-info":[{"award-number":["SFB-TRR57\/P06"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["LU 1360\/3-1"],"award-info":[{"award-number":["LU 1360\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC1380\/A01"],"award-info":[{"award-number":["CRC1380\/A01"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CA 830\/3-1"],"award-info":[{"award-number":["CA 830\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Liver disease and depression are known to be closely associated. Non-invasive tests (NIT), such as the FIB-4 score, have been recommended by different guidelines to rule out advanced fibrosis and to stratify the risk of liver-related outcomes in patients with chronic liver diseases. However, the predictive value of an elevated FIB-4 score regarding the development of depression and\/or anxiety disorders among the general population is unknown. Methods: By using the Disease Analyzer database (IQVIA), which compiles diagnoses and laboratory values as well as basic medical and demographic data of patients followed in general practices in Germany, we identified 370,756 patients with available lab values for FIB-4 score calculation between 2005 and 2019. Patients with an FIB-4 score &lt; 2 were matched 1:1 to patients with an FIB-4 index \u2265 2 by age, sex and yearly consultation frequency. Results: In regression analysis, the incidence rate ratio (IRR) of depression was significantly higher among patients with an FIB-4 score \u2265 2.0 compared to patients with a lower FIB-4 score &lt;2.0 (IRR: 1.12, p &lt; 0.001). This association was significant for both female (IRR: 1.10, p = 0.004) and male (IRR: 1.15, p &lt; 0.001) patients and strongest in the age groups \u226450 years (IRR: 1.42, p &lt; 0.001) and 51-60 years (IRR: 1.34, p &lt; 0.001). There was no significant association between an elevated FIB-4 score \u2265 2.0 and the incidence of depression among patients aged 60 years and older. There was no significant increase in the IRR of anxiety disorders for patients with high or low FIB-4 scores. Conclusion: Our study suggests a previously unknown association between an elevated FIB-4 score and an increased incidence of depression. This finding suggests that the FIB-4 score is not only a valuable tool for the prediction of liver-specific endpoints but also may be of relevance for the prediction of extrahepatic comorbidities, which in turn may argue for clinical screening programs in patients with an elevated FIB-4.<\/jats:p>","DOI":"10.3390\/jcm11082214","type":"journal-article","created":{"date-parts":[[2022,4,18]],"date-time":"2022-04-18T04:21:28Z","timestamp":1650255688000},"page":"2214","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["An Elevated FIB-4 Score Is Associated with an Increased Incidence of Depression among Outpatients in Germany"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2736-9778","authenticated-orcid":false,"given":"David","family":"Sch\u00f6ler","sequence":"first","affiliation":[{"name":"Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University D\u00fcsseldorf, Moorenstrasse 5, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2124-7227","authenticated-orcid":false,"given":"Karel","family":"Kostev","sequence":"additional","affiliation":[{"name":"Epidemiology, IQVIA, 60549 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00fcnevver","family":"Demir","sequence":"additional","affiliation":[{"name":"Clinic for Hepatology and Gastroenterology, Charit\u00e9 University Medical Center, Augustenburger Platz 1, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8149-8087","authenticated-orcid":false,"given":"Mark","family":"Luedde","sequence":"additional","affiliation":[{"name":"KGP Bremerhaven, 27574 Bremerhaven, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6798-5092","authenticated-orcid":false,"given":"Marcel","family":"Konrad","sequence":"additional","affiliation":[{"name":"FOM University of Applied Sciences for Economics and Management, 60549 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Luedde","sequence":"additional","affiliation":[{"name":"Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University D\u00fcsseldorf, Moorenstrasse 5, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Roderburg","sequence":"additional","affiliation":[{"name":"Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University D\u00fcsseldorf, Moorenstrasse 5, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2799-2287","authenticated-orcid":false,"given":"Sven H.","family":"Loosen","sequence":"additional","affiliation":[{"name":"Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University D\u00fcsseldorf, Moorenstrasse 5, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,15]]},"reference":[{"key":"ref_1","first-page":"12","article-title":"Depressionen und Lebererkrankungen: Die Rolle von Mikrobiom und Inflammation","volume":"87","author":"Kahl","year":"2018","journal-title":"Fortschr. Neurol. Psychiatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1111\/j.1360-0443.2010.03351.x","article-title":"Alcohol and depression","volume":"106","author":"Boden","year":"2011","journal-title":"Addiction"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"207","DOI":"10.2174\/1574886311308030011","article-title":"Liver injury associated with antidepressants","volume":"8","author":"Park","year":"2013","journal-title":"Curr. Drug Saf."},{"key":"ref_4","first-page":"535","article-title":"Frequency of Depression Among Patients With Chronic Liver Disease","volume":"32","author":"Khan","year":"2020","journal-title":"J. Ayub Med. Coll. Abbottabad."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/mp.2016.44","article-title":"Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host\u2019s metabolism","volume":"21","author":"Zheng","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1002\/jnr.24476","article-title":"The role of inflammation and the gut microbiome in depression and anxiety","volume":"97","author":"Peirce","year":"2019","journal-title":"J. Neurosci. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/7854_2016_37","article-title":"Immune-to-brain communication pathways in inflammation-associated sickness and depression","volume":"31","author":"Swain","year":"2016","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7902874","DOI":"10.1155\/2019\/7902874","article-title":"The Gut Microbiome Modulates the Changes in Liver Metabolism and in Inflammatory Processes in the Brain of Chronic Unpredictable Mild Stress Rats","volume":"2019","author":"Lv","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Liang, S., Wu, X., Hu, X., Wang, T., and Jin, F. (2018). Recognizing Depression from the Microbiota\u2013Gut\u2013Brain Axis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061592"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.tins.2013.01.005","article-title":"Gut\u2013brain axis: How the microbiome influences anxiety and depression","volume":"36","author":"Foster","year":"2013","journal-title":"Trends Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1002\/hep.21178","article-title":"Development of a simple noninvasive index to predict significant fibrosis in patients with HIV\/HCV coinfection","volume":"43","author":"Sterling","year":"2006","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1136\/gutjnl-2017-314924","article-title":"Guidelines on the management of abnormal liver blood tests","volume":"67","author":"Newsome","year":"2018","journal-title":"Gut."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1016\/S0140-6736(18)31948-2","article-title":"Depression","volume":"392","author":"Malhi","year":"2018","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"E1304","DOI":"10.1503\/cmaj.170125","article-title":"Depression and mortality in a longitudinal study: 1952\u20132011","volume":"189","author":"Gilman","year":"2017","journal-title":"Can. Med. Assoc. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"459","DOI":"10.5414\/CP203320","article-title":"Basic characteristics and representativeness of the German Disease Analyzer database","volume":"56","author":"Rathmann","year":"2018","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.jhep.2021.08.030","article-title":"An elevated FIB-4 score predicts liver cancer development: A longitudinal analysis from 29,999 patients with NAFLD","volume":"76","author":"Loosen","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e112","DOI":"10.1093\/eurjpc\/zwab048","article-title":"Heart failure and depression: A comparative analysis with different types of cancer","volume":"29","author":"Loosen","year":"2022","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.jpsychires.2021.10.033","article-title":"Age effects on treatment patterns in 138,097 patients with unipolar depression followed in general practices in Germany","volume":"144","author":"Kostev","year":"2021","journal-title":"J. Psychiatr. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1097\/01.mlr.0000182534.19832.83","article-title":"Coding Algorithms for Defining Comorbidities in ICD-9-CM and ICD-10 Administrative Data","volume":"43","author":"Quan","year":"2005","journal-title":"Med. Care"},{"key":"ref_20","unstructured":"(2018). Global Burden of Disease Collaborative Network. Global Burden of Disease Study 2017 (GBD 2017) Results, Institute for Health Metrics and Evaluation (IHME). Available online: http:\/\/ghdx.healthdata.org\/gbd-results-tool."},{"key":"ref_21","first-page":"1560","article-title":"Socio-economic variations in the mental health treatment gap for people with anxiety, mood, and substance use disorders: Results from the WHO World Mental Health (WMH) surveys","volume":"48","author":"Alonso","year":"2017","journal-title":"Psychol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1046\/j.1525-1497.1999.03478.x","article-title":"Awareness, diagnosis, and treatment of depression","volume":"14","author":"Goldman","year":"1999","journal-title":"J. Gen. Intern. Med."},{"key":"ref_23","first-page":"1215","article-title":"Early detection of depression by primary care physicians","volume":"142","author":"Feightner","year":"1990","journal-title":"Can. Med. Assoc. J."},{"key":"ref_24","first-page":"469","article-title":"Early detection of depression in young and elderly people","volume":"44","author":"Garland","year":"2002","journal-title":"Br. Columbia Med. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.jad.2016.03.025","article-title":"A randomised controlled trial of the effectiveness of a program for early detection and treatment of depression in primary care","volume":"198","author":"Picardi","year":"2016","journal-title":"J. Affect. Disord."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Richter, T., Fishbain, B., Richter-Levin, G., and Okon-Singer, H. (2021). Machine Learning-Based Behavioral Diagnostic Tools for Depression: Advances, Challenges, and Future Directions. J. Pers. Med., 11.","DOI":"10.3390\/jpm11100957"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e12554","DOI":"10.2196\/12554","article-title":"Early Detection of Depression: Social Network Analysis and Random Forest Techniques","volume":"21","author":"Cacheda","year":"2019","journal-title":"J. Med. Internet Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.jhep.2021.05.025","article-title":"EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis\u20142021 update","volume":"75","author":"Berzigotti","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.jad.2008.06.026","article-title":"The PHQ-8 as a measure of current depression in the general population","volume":"114","author":"Kroenke","year":"2009","journal-title":"J. Affect. Disord."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6141","DOI":"10.3748\/wjg.v26.i40.6141","article-title":"Role of gut microbiota via the gut-liver-brain axis in digestive diseases","volume":"26","author":"Ding","year":"2020","journal-title":"World J. Gastroenterol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Gupta, H., Suk, K.T., and Kim, D.J. (2021). Gut Microbiota at the Intersection of Alcohol, Brain, and the Liver. J. Clin. Med., 10.","DOI":"10.3390\/jcm10030541"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Lee, J.S., O\u2019Connell, E.M., Pacher, P., and Lohoff, F.W. (2021). PCSK9 and the Gut-Liver-Brain Axis: A Novel Therapeutic Target for Immune Regulation in Alcohol Use Disorder. J. Clin. Med., 10.","DOI":"10.3390\/jcm10081758"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"533","DOI":"10.2174\/1570159X15666171123201142","article-title":"Imaging the role of inflammation in mood and anxiety-related disorders","volume":"16","author":"Felger","year":"2017","journal-title":"Curr. Neuropharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1186\/1741-7015-11-200","article-title":"So depression is an inflammatory disease, but where does the inflammation come from?","volume":"11","author":"Berk","year":"2013","journal-title":"BMC Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1002\/cpt.1870","article-title":"The Microbiome and the Gut-Liver-Brain Axis for Central Nervous System Clinical Pharmacology: Challenges in Specifying and Integrating In Vitro and In Silico Models","volume":"108","author":"Hawkins","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/s41586-019-1742-x","article-title":"Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease","volume":"575","author":"Duan","year":"2019","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e04097","DOI":"10.1016\/j.heliyon.2020.e04097","article-title":"Crosstalk between the microbiota-gut-brain axis and depression","volume":"6","author":"Du","year":"2020","journal-title":"Heliyon"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1146\/annurev-pharmtox-010919-023628","article-title":"Microbiota-Gut-Brain Axis: New Therapeutic Opportunities","volume":"60","author":"Clarke","year":"2020","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.3389\/fpsyt.2021.651536","article-title":"Gut Microbiome: A Potential Indicator for Differential Diagnosis of Major Depressive Disorder and General Anxiety Disorder","volume":"12","author":"Dong","year":"2021","journal-title":"Front. Psychiatry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1002\/j.2051-5545.2008.tb00180.x","article-title":"The unique challenges of managing depression in mid-life women","volume":"7","author":"Dennerstein","year":"2008","journal-title":"World Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"244","DOI":"10.3109\/13697137.2010.510912","article-title":"Prevalence of depression among postmenopausal women and related characteristics","volume":"14","author":"Unsal","year":"2010","journal-title":"Climacteric"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Comijs, H.C., Van Marwijk, H.W., Van Der Mast, R.C., Naarding, P., Oude Voshaar, R.C., Beekman, A.T.F., Boshuisen, M., Dekker, J., Kok, R., and De Waal, M.W.M. (2011). The Netherlands study of depression in older persons (NESDO); A prospective cohort study. BMC Res. Notes, 4.","DOI":"10.1186\/1756-0500-4-524"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1001\/jamapsychiatry.2018.0190","article-title":"Association of Depression and Anxiety Disorders With Autoimmune Thyroiditis","volume":"75","author":"Siegmann","year":"2018","journal-title":"JAMA Psychiatry"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"45768","DOI":"10.18632\/oncotarget.17470","article-title":"Impact of age on the diagnostic performances and cut-offs of APRI and FIB-4 for significant fibrosis and cirrhosis in chronic hepatitis B","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s12264-021-00638-3","article-title":"Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications","volume":"37","author":"Li","year":"2021","journal-title":"Neurosci. Bull."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1038\/ng.3623","article-title":"Identification of 15 genetic loci associated with risk of major depression in individuals of European descent","volume":"48","author":"Hyde","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Nobis, A., Zalewski, D., and Waszkiewicz, N. (2020). Peripheral Markers of Depression. J. Clin. Med., 9.","DOI":"10.3390\/jcm9123793"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/8\/2214\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:54:43Z","timestamp":1760136883000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/8\/2214"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,15]]},"references-count":47,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["jcm11082214"],"URL":"https:\/\/doi.org\/10.3390\/jcm11082214","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,15]]}}}