{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T20:46:03Z","timestamp":1783975563662,"version":"3.55.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:00:00Z","timestamp":1656633600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>A variant (p.Arg225Trp) of peroxisomal acyl\u2010CoA oxidase 2 (ACOX2), involved in bile acid (BA) side\u2010chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27\u2010BAs, mainly 3\u03b1,7\u03b1,12\u03b1\u2010trihydroxy\u20105\u03b2\u2010cholestanoic acid (THCA). We aimed to investigate the prevalence of ACOX2 deficiency\u2010associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p>Among 33 patients with unexplained hypertransaminasemia from 11 hospitals and 13 of their relatives, seven individuals with abnormally high C27\u2010BA levels (&gt;50% of total BAs) were identified by high\u2010performance liquid chromatography\u2010mass spectrometry. The p.Arg225Trp variant was found in homozygosity (exon amplification\/sequencing) in two patients and three family members. Two additional nonrelated patients were heterozygous carriers of different alleles: c.673C&gt;T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In patients with ADAH, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized aminotransferase levels. Incubation of HuH\u20107 hepatoma cells with THCA, which was efficiently taken up, but not through BA transporters, increased reactive oxygen species production (flow cytometry), endoplasmic reticulum stress biomarkers (<jats:italic toggle=\"yes\">GRP78<\/jats:italic>, <jats:italic toggle=\"yes\">CHOP<\/jats:italic>, and <jats:italic toggle=\"yes\">XBP1\u2010S\/XBP1\u2010U<\/jats:italic> ratio), and <jats:italic toggle=\"yes\">BAX\u03b1<\/jats:italic> expression (reverse transcription followed by quantitative polymerase chain reaction and immunoblot), whereas cell viability was decreased (tetrazolium salt\u2010based cell viability test). THCA\u2010induced cell toxicity was higher than that of major C24\u2010BAs and was not prevented by UDCA. Fourteen predicted <jats:italic toggle=\"yes\">ACOX2<\/jats:italic> variants were generated (site\u2010directed mutagenesis) and expressed in HuH\u20107 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a noninvasive diagnostic strategy based on plasma BA profiling and <jats:italic toggle=\"yes\">ACOX2<\/jats:italic> sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32517","type":"journal-article","created":{"date-parts":[[2022,4,8]],"date-time":"2022-04-08T20:59:43Z","timestamp":1649451583000},"page":"1259-1274","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":23,"title":["Beneficial effect of ursodeoxycholic acid in patients with acyl\u2010CoA oxidase 2 (ACOX2) deficiency\u2013associated hypertransaminasemia"],"prefix":"10.1097","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0934-2202","authenticated-orcid":false,"given":"Marta","family":"Alonso\u2010Pe\u00f1a","sequence":"first","affiliation":[{"name":"Experimental Hepatology and Drug Targeting,Institute for Biomedical Research,University of Salamanca,Salamanca,Spain"},{"name":"Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases,Valdecilla Research Institute (IDIVAL),Marqu\u00e9s de Valdecilla University Hospital,Santander,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Espinosa\u2010Escudero","sequence":"additional","affiliation":[{"name":"Experimental Hepatology and Drug Targeting,Institute for Biomedical Research,University of Salamanca,Salamanca,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Herraez","sequence":"additional","affiliation":[{"name":"Experimental Hepatology and Drug Targeting,Institute for Biomedical Research,University of Salamanca,Salamanca,Spain"},{"name":"Center for the Study of Liver and Gastrointestinal Diseases (CIBEREHD),Carlos III National Institute of Health,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Briz","sequence":"additional","affiliation":[{"name":"Experimental Hepatology and Drug Targeting,Institute for Biomedical Research,University of Salamanca,Salamanca,Spain"},{"name":"Center for the Study of Liver and Gastrointestinal Diseases (CIBEREHD),Carlos III National Institute of Health,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luisa","family":"Cagigal","sequence":"additional","affiliation":[{"name":"Pathological Anatomy Service,Hospital Universitario Marqu\u00e9s de Valdecilla,Santander,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4667-4492","authenticated-orcid":false,"given":"Jesus M.","family":"Gonzalez\u2010Santiago","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital of Salamanca,Institute for Biomedical Research,Salamanca,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida","family":"Ortega\u2010Alonso","sequence":"additional","affiliation":[{"name":"Liver Unit, Gastroenterology Service,Institute of Biomedical Research of M\u00e1laga,School of Medicine,University Hospital Virgen de la Victoria,M\u00e1laga,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conrado","family":"Fernandez\u2010Rodriguez","sequence":"additional","affiliation":[{"name":"Gastroenterology Unit,Fundaci\u00f3n Hospital Alcorc\u00f3n,Rey Juan Carlos University,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Bujanda","sequence":"additional","affiliation":[{"name":"Center for the Study of Liver and Gastrointestinal Diseases (CIBEREHD),Carlos III National Institute of Health,Madrid,Spain"},{"name":"Department of Liver and Gastrointestinal Diseases,Biodonostia Health Research Institute,Donostia University Hospital,University of the Basque Country,San Sebastian,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Calvo Sanchez","sequence":"additional","affiliation":[{"name":"Segovia General 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(IDIBAPS),Barcelona,Spain"},{"name":"Consejo Superior de Investigaciones Cient\u00edficas (CSIC),Madrid,Spain"},{"name":"Research Center for Alcoholic Liver and Pancreatic Diseases (ALPD) and Cirrhosis,Keck School of Medicine,University of Southern California,Los Angeles,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raul J.","family":"Andrade","sequence":"additional","affiliation":[{"name":"Center for the Study of Liver and Gastrointestinal Diseases (CIBEREHD),Carlos III National Institute of Health,Madrid,Spain"},{"name":"Liver Unit, Gastroenterology Service,Institute of Biomedical Research of M\u00e1laga,School of Medicine,University Hospital Virgen de la Victoria,M\u00e1laga,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Lammert","sequence":"additional","affiliation":[{"name":"Department of Medicine II,Saarland University Medical Center,Homburg,Germany"},{"name":"Health Sciences,Hannover Medical 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