{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T23:03:31Z","timestamp":1794006211235,"version":"4.8.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2020,3,16]],"date-time":"2020-03-16T00:00:00Z","timestamp":1584316800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:p>Yellow fever (YF) is a viral hemorrhagic fever that typically involves the liver. Brazil recently experienced its largest recorded YF outbreak, and the disease was fatal in more than a third of affected individuals, mostly because of acute liver failure. Affected individuals are generally treated only supportively, but during the recent Brazilian outbreak, selected patients were treated with liver transplant. We took advantage of this clinical experience to better characterize the clinical and pathological features of YF\u2010induced liver failure and to examine the mechanism of hepatocellular injury in YF, to identify targets that would be amenable to therapeutic intervention in preventing progression to liver failure and death. Patients with YF liver failure rapidly developed massive transaminase elevations, with jaundice, coagulopathy, thrombocytopenia, and usually hepatic encephalopathy, along with pathological findings that included microvesicular steatosis and lytic necrosis. Hepatocytes began to express the type 3 isoform of the inositol trisphosphate receptor (ITPR3), an intracellular calcium (Ca<jats:sup>2+<\/jats:sup>) channel that is not normally expressed in hepatocytes. Experiments in an animal model, isolated hepatocytes, and liver\u2010derived cell lines showed that this new expression of ITPR3 was associated with increased nuclear Ca<jats:sup>2+<\/jats:sup> signaling and hepatocyte proliferation, and reduced steatosis and cell death induced by the YF virus. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Yellow fever often induces liver failure characterized by massive hepatocellular damage plus steatosis. New expression of ITPR3 also occurs in YF\u2010infected hepatocytes, which may represent an endogenous protective mechanism that could suggest approaches to treat affected individuals before they progress to liver failure, thereby decreasing the mortality of this disease in a way that does not rely on the costly and limited resource of liver transplantation.<\/jats:p>","DOI":"10.1002\/hep4.1504","type":"journal-article","created":{"date-parts":[[2020,3,16]],"date-time":"2020-03-16T08:39:13Z","timestamp":1584347953000},"page":"657-669","source":"Crossref","is-referenced-by-count":22,"title":["Molecular Mechanism for Protection Against Liver Failure in Human Yellow Fever Infection"],"prefix":"10.1097","volume":"4","author":[{"given":"Fernanda de Oliveira","family":"Lemos","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics,Universidade Federal de Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andressa","family":"Fran\u00e7a","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics,Universidade Federal de Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ant\u00f4nio Carlos Melo","family":"Lima Filho","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics,Universidade Federal de Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo M.","family":"Florentino","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics,Universidade Federal de Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcone Loiola","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics,Universidade Federal de Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dabny G.","family":"Missiaggia","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics,Universidade Federal de Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisele Olinto Libanio","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Immunology,Universidade Federal de Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3493-6929","authenticated-orcid":false,"given":"Felipe Ferraz","family":"Dias","sequence":"additional","affiliation":[{"name":"Center of Microscopy,Universidade Federal de Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingredy Beatriz","family":"Souza Passos","sequence":"additional","affiliation":[{"name":"Department of Morphology,Universidade Federal de Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro M.","family":"Teixeira","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Immunology,Universidade Federal de Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ant\u00f4nio M\u00e1rcio de Faria","family":"Andrade","sequence":"additional","affiliation":[{"name":"Hepatic Transplant Service,Hospital Fel\u00edcio Rocho,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiano Xavier","family":"Lima","sequence":"additional","affiliation":[{"name":"Hepatic Transplant Service,Hospital Fel\u00edcio Rocho,Belo Horizonte,Brazil"},{"name":"Surgery,Universidade Federal de Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula Vieira Teixeira","family":"Vidigal","sequence":"additional","affiliation":[{"name":"Pathological Anatomy and Forensic Medicine,Universidade Federal de Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian Vasconcelos","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Morphology,Universidade Federal de Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matheus Castro","family":"Fonseca","sequence":"additional","affiliation":[{"name":"Brazilian Biosciences National Laboratory (LNBio),Brazilian Center for Research in Energy and Materials,Rua Giuseppe M\u00e1ximo Scolfaro,Campinas,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Nathanson","sequence":"additional","affiliation":[{"name":"Section of Digestive Diseases,Department of Internal Medicine,Yale University School of Medicine,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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