{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T05:09:12Z","timestamp":1785474552857,"version":"3.56.0"},"reference-count":39,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T00:00:00Z","timestamp":1620086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Associazione Unitaria Avvocati e Procuratori di Stato","award":["000"],"award-info":[{"award-number":["000"]}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["COVID-2020-12371817"],"award-info":[{"award-number":["COVID-2020-12371817"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["COVID-2020-12371675"],"award-info":[{"award-number":["COVID-2020-12371675"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Liver injury in COVID-19 patients has progressively emerged, even in those without a history of liver disease, yet the mechanism of liver pathogenicity is still controversial. COVID-19 is frequently associated with increased serum ferritin levels, and hyperferritinemia was shown to correlate with illness severity. The liver is the major site for iron storage, and conditions of iron overload have been established to have a pathogenic role in development of liver diseases. We presented here six patients who developed severe COVID-19, with biochemical evidence of liver failure. Three cases were survived patients, who underwent liver biopsy; the other three were deceased patients, who were autopsied. None of the patients suffered underlying liver pathologies. Histopathological and ultrastructural analyses were performed. The most striking finding we demonstrated in all patients was iron accumulation into hepatocytes, associated with degenerative changes. Abundant ferritin particles were found enclosed in siderosomes, and large aggregates of hemosiderin were found, often in close contact with damaged mitochondria. Iron-caused oxidative stress may be responsible for mitochondria metabolic dysfunction. In agreement with this, association between mitochondria and lipid droplets was also found. Overall, our data suggest that hepatic iron overload could be the pathogenic trigger of liver injury associated to COVID-19.<\/jats:p>","DOI":"10.3390\/cells10051103","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T11:06:01Z","timestamp":1620212761000},"page":"1103","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Hepatic Failure in COVID-19: Is Iron Overload the Dangerous Trigger?"],"prefix":"10.3390","volume":"10","author":[{"given":"Franca","family":"Del Nonno","sequence":"first","affiliation":[{"name":"Pathology Unit, National Institute for Infectious Diseases \u201cLazzaro Spallanzani\u201d-IRCCS, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9209-1207","authenticated-orcid":false,"given":"Roberta","family":"Nardacci","sequence":"additional","affiliation":[{"name":"Laboratory of Electron Microscopy, National Institute for Infectious Diseases \u201cLazzaro Spallanzani\u201d-IRCCS, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Colombo","sequence":"additional","affiliation":[{"name":"Pathology Unit, National Institute for Infectious Diseases \u201cLazzaro Spallanzani\u201d-IRCCS, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ubaldo","family":"Visco-Comandini","sequence":"additional","affiliation":[{"name":"Hepatology Unit \u201cLazzaoro Spallanzani\u201d-IRCCS, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Cicalini","sequence":"additional","affiliation":[{"name":"HIV\/AIDS Department, National Institute for Infectious Diseases \u201cLazzaro Spallanzani\u201d-IRCCS, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Antinori","sequence":"additional","affiliation":[{"name":"HIV\/AIDS Department, National Institute for Infectious Diseases \u201cLazzaro Spallanzani\u201d-IRCCS, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Marchioni","sequence":"additional","affiliation":[{"name":"Clinical Department, National Institute for Infectious Diseases \u201cLazzaro Spallanzani\u201d-IRCCS, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianpiero","family":"D\u2019Offizi","sequence":"additional","affiliation":[{"name":"Hepatology Unit \u201cLazzaoro Spallanzani\u201d-IRCCS, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Piacentini","sequence":"additional","affiliation":[{"name":"Laboratory of Electron Microscopy, National Institute for Infectious Diseases \u201cLazzaro Spallanzani\u201d-IRCCS, 00149 Rome, Italy"},{"name":"Department of Biology, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8752-2415","authenticated-orcid":false,"given":"Laura","family":"Falasca","sequence":"additional","affiliation":[{"name":"Laboratory of Electron Microscopy, National Institute for Infectious Diseases \u201cLazzaro Spallanzani\u201d-IRCCS, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/S0140-6736(20)30211-7","article-title":"Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study","volume":"395","author":"Chen","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2620","DOI":"10.1172\/JCI137244","article-title":"Clinical and immunological features of severe and moderate coronavirus disease-2019","volume":"130","author":"Chen","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1093\/infdis\/jiaa578","article-title":"Postmortem Findings in Italian Patients with COVID-19: A Descriptive Full Autopsy Study of Cases with and without Comorbidities","volume":"222","author":"Falasca","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/S2468-1253(20)30126-6","article-title":"Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: A systematic review and meta-analysis","volume":"5","author":"Mao","year":"2020","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1111\/liv.14435","article-title":"Liver injury during highly pathogenic human coronavirus infections","volume":"40","author":"Xu","year":"2020","journal-title":"Liver Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1007\/s12072-020-10075-5","article-title":"Clinical characteristics and risk factors of liver injury in COVID-19: A retrospective cohort study from Wuhan, China","volume":"14","author":"Chen","year":"2020","journal-title":"Hepatol. Int."},{"key":"ref_7","first-page":"1","article-title":"COVID-19-associated liver injury: From bedside to bench","volume":"1","author":"Li","year":"2021","journal-title":"J. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1186\/s12931-020-01546-2","article-title":"Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients' performance: A prospective observational cohort study","volume":"21","author":"Sonnweber","year":"2020","journal-title":"Respir. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Bellmann-Weiler, R., Lanser, L., Barket, R., Rangger, L., Schapfl, A., Schaber, M., Fritsche, G., W\u00f6ll, E., and Weiss, G. (2020). Prevalence and Predictive Value of Anemia and Dysregulated Iron Homeostasis in Patients with COVID-19 Infection. J. Clin. Med., 9.","DOI":"10.3390\/jcm9082429"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/hep.24330","article-title":"Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases","volume":"54","author":"Bacon","year":"2011","journal-title":"Hepatology"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Bloomer, S.A., and Brown, K.E. (2019). Iron-Induced Liver Injury: A Critical Reappraisal. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092132"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4746","DOI":"10.3748\/wjg.v13.i35.4746","article-title":"Role of iron in hepatic fibrosis: One piece in the puzzle","volume":"13","author":"Philippe","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/0168-8278(95)80226-6","article-title":"Histological grading and staging of chronic hepatitis","volume":"22","author":"Ishak","year":"1995","journal-title":"J. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/path.1700840107","article-title":"Hepatic pathology in relatives of patients with haemochromatosis","volume":"84","author":"Scheuer","year":"1962","journal-title":"J. Pathol. Bacteriol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.bbamcr.2006.04.006","article-title":"Structure and dynamics of the mitochondrial inner membrane cristae","volume":"1763","author":"Mannella","year":"2006","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/S2468-1253(20)30057-1","article-title":"Liver injury in COVID-19: Management and challenges","volume":"5","author":"Zhang","year":"2020","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.jhep.2020.04.006","article-title":"COVID-19: Abnormal liver function tests","volume":"73","author":"Cai","year":"2020","journal-title":"J. Hepatol"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1002\/hep.31326","article-title":"Liver Biochemistries in Hospitalized Patients with COVID-19","volume":"73","author":"Bloom","year":"2020","journal-title":"Hepatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1002\/hep.31404","article-title":"Acute Liver Injury in COVID-19: Prevalence and Association with Clinical Outcomes in a Large U.S. Cohort","volume":"72","author":"Phipps","year":"2020","journal-title":"Hepatology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1038\/s41379-020-00649-x","article-title":"Hepatic pathology in patients dying of COVID-19: A series of 40 cases including clinical, histologic, and virologic data","volume":"33","author":"Lagana","year":"2020","journal-title":"Mod. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry De-pends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1111\/liv.14500","article-title":"SARS-CoV-2 virus and liver expression of host receptors: Putative mechanisms of liver involvement in COVID-19","volume":"40","author":"Pirola","year":"2020","journal-title":"Liver Int."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Chai, X., Hu, L., Zhang, Y., Han, W., Lu, Z., and Ke, A. (2020). Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. Bio-Rxiv.","DOI":"10.1101\/2020.02.03.931766"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s13238-020-00718-6","article-title":"Recapitulation of SARS-CoV-2 infection and cholangiocyte damage with human liver ductal organoids","volume":"11","author":"Zhao","year":"2020","journal-title":"Protein Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.jhep.2020.05.025","article-title":"SARS-CoV-2 related liver impairment\u2014Perception may not be the reality","volume":"73","author":"Philips","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.cell.2021.01.004","article-title":"Multi-organ proteomic landscape of COVID-19 autopsies","volume":"184","author":"Nie","year":"2021","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1097\/00000441-199101000-00006","article-title":"Iron and the liver","volume":"301","author":"Bonkovsky","year":"1991","journal-title":"Am. J. Med. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1152\/physrev.00008.2013","article-title":"Systemic iron homeostasis","volume":"93","author":"Ganz","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"109230","DOI":"10.1016\/j.cbi.2020.109230","article-title":"Taxifolin ameliorates iron overload-induced hepatocellular injury: Modulating PI3K\/AKT and p38 MAPK signaling, inflammatory response, and hepatocellular regeneration","volume":"330","author":"Salama","year":"2020","journal-title":"Chem. Biol. Interact."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.biochi.2015.06.006","article-title":"Glutamyl cysteine dipeptide suppresses ferritin expression and alleviates liver injury in iron-overload rat model","volume":"115","author":"Salama","year":"2015","journal-title":"Biochimie"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1002\/hep.1840030216","article-title":"The amount of ferritin and hemosiderin in the livers of patients with iron-loading diseases","volume":"3","author":"Zuyderhoudt","year":"1983","journal-title":"Hepatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/s41580-020-00324-8","article-title":"Ferroptosis: Mechanisms, biology and role in disease","volume":"22","author":"Jiang","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.arcmed.2020.04.019","article-title":"Oxidative Stress as Key Player in Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection","volume":"51","author":"Mesta","year":"2020","journal-title":"Arch. Med. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1089\/ars.2007.2000","article-title":"Ultrastructure of the mitochondrion and its bearing on function and bioenergetics","volume":"10","author":"Benard","year":"2008","journal-title":"Antioxid Redox Signal."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Javadov, S., Kozlov, A.V., and Camara, A.K.S. (2020). Mitochondria in Health and Diseases. Cells, 9.","DOI":"10.3390\/cells9051177"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"327167","DOI":"10.1155\/2013\/327167","article-title":"Mitochondrial dysfunction induces formation of lipid droplets as a generalized response to stress","volume":"2013","author":"Lee","year":"2013","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41419-021-03527-9","article-title":"Evidences for lipid involvement in SARS-CoV-2 cytopathogenesis","volume":"12","author":"Nardacci","year":"2021","journal-title":"Cell Death Dis."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/5\/1103\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:57:09Z","timestamp":1760162229000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/5\/1103"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,4]]},"references-count":39,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["cells10051103"],"URL":"https:\/\/doi.org\/10.3390\/cells10051103","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,4]]}}}