{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:27:38Z","timestamp":1792006058575,"version":"4.4.0"},"reference-count":50,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T00:00:00Z","timestamp":1617926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Animals"],"abstract":"<jats:p>Facial eczema (FE) is a secondary photosensitization disease of farm ruminants caused by the sporidesmin A, produced in the spores of the saprophytic fungus Pithomyces chartarum. This study communicates an outbreak of ovine FE in Asturias (Spain) and characterizes the serum biochemical pattern and the immune response that may contribute to liver damage, favoring cholestasis and the progression to fibrosis and cirrhosis. Animals showed clinical signs of photosensitivity, with decrease of daily weight gain and loss of wool and crusting for at least 6 months after the FE outbreak. Serum activity of \u03b3-glutamyltransferase and alkaline phosphatase were significantly increased in sheep with skin lesions. In the acute phase, edematous skin lesions in the head, hepatocytic and canalicular cholestasis in centrilobular regions, presence of neutrophils in small clumps surrounding deposits of bile pigment, ductular proliferation, as well as cholemic nephrosis, were observed. Macrophages, stained positively for MAC387, were found in areas of canalicular cholestasis. In the chronic phase, areas of alopecia and crusting were seen in the head, and the liver was atrophic with large regeneration nodules and gallstones. Fibrosis around dilated bile ducts, \u201ctypical\u201d and \u201catypical\u201d ductular reaction and an inflammatory infiltrate composed of lymphocytes and pigmented macrophages, with iron deposits and lipofuscin, were found. The surviving parenchyma persisted with a jigsaw pattern characteristic of biliary cirrhosis. Concentric and eccentric myointimal proliferation was found in arteries near damaged bile ducts. In cirrhotic livers, stellated cells, ductular reaction, ectatic bile ducts and presence of M2 macrophages and lymphocytes, were observed in areas of bile ductular reaction.<\/jats:p>","DOI":"10.3390\/ani11041070","type":"journal-article","created":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T10:05:21Z","timestamp":1617962721000},"page":"1070","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Pathological Study of Facial Eczema (Pithomycotoxicosis) in Sheep"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4690-7770","authenticated-orcid":false,"given":"Miguel","family":"Fern\u00e1ndez","sequence":"first","affiliation":[{"name":"Departamento de Sanidad Animal, Facultad de Veterinaria, Universidad de Le\u00f3n, C\/Prof. Pedro C\u00e1rmenes s\/n, E-24071 Le\u00f3n, Spain"},{"name":"Instituto de Ganader\u00eda de Monta\u00f1a (IGM), CSIC-Universidad de Le\u00f3n, Finca Marzanas s\/n, E-24346 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0075-1587","authenticated-orcid":false,"given":"Valent\u00edn","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Departamento de Sanidad Animal, Facultad de Veterinaria, Universidad de Le\u00f3n, C\/Prof. Pedro C\u00e1rmenes s\/n, E-24071 Le\u00f3n, Spain"},{"name":"Instituto de Ganader\u00eda de Monta\u00f1a (IGM), CSIC-Universidad de Le\u00f3n, Finca Marzanas s\/n, E-24346 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5454-0078","authenticated-orcid":false,"given":"Miguel","family":"Fuertes","sequence":"additional","affiliation":[{"name":"Department of Animal Health, NEIKER-Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), Parque Cient\u00edfico y Tecnol\u00f3gico de Bizkaia, P812, E-48160 Derio, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Benavides","sequence":"additional","affiliation":[{"name":"Instituto de Ganader\u00eda de Monta\u00f1a (IGM), CSIC-Universidad de Le\u00f3n, Finca Marzanas s\/n, E-24346 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9036-1402","authenticated-orcid":false,"given":"Jos\u00e9","family":"Espinosa","sequence":"additional","affiliation":[{"name":"Departamento de Sanidad Animal, Facultad de Veterinaria, Universidad de Le\u00f3n, C\/Prof. Pedro C\u00e1rmenes s\/n, E-24071 Le\u00f3n, Spain"},{"name":"Instituto de Ganader\u00eda de Monta\u00f1a (IGM), CSIC-Universidad de Le\u00f3n, Finca Marzanas s\/n, E-24346 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Men\u00e9ndez","sequence":"additional","affiliation":[{"name":"Area de Sistemas de Producci\u00f3n Animal, Servicio Regional de Investigaci\u00f3n y Desarrollo Agroalimentario, SERIDA, E-33300 Villaviciosa, Asturias, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7404-1380","authenticated-orcid":false,"given":"Ana L.","family":"Garc\u00eda-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Animal Health, NEIKER-Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), Parque Cient\u00edfico y Tecnol\u00f3gico de Bizkaia, P812, E-48160 Derio, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Carmen","family":"Ferreras","sequence":"additional","affiliation":[{"name":"Departamento de Sanidad Animal, Facultad de Veterinaria, Universidad de Le\u00f3n, C\/Prof. Pedro C\u00e1rmenes s\/n, E-24071 Le\u00f3n, Spain"},{"name":"Instituto de Ganader\u00eda de Monta\u00f1a (IGM), CSIC-Universidad de Le\u00f3n, Finca Marzanas s\/n, E-24346 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1080\/00480169.1991.35650","article-title":"Facial eczema in goats: The toxicity of sporidesmin in goats and its pathology","volume":"39","author":"Smith","year":"1991","journal-title":"N. Z. Vet. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1099\/mic.0.27847-0","article-title":"The epipolythiodioxopiperazine (ETP) class of fungal toxins: Distribution, mode of action, functions and biosynthesis","volume":"151","author":"Gardiner","year":"2005","journal-title":"Microbiology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1177\/1040638713504572","article-title":"Mycotoxicoses of ruminants and horses","volume":"25","author":"Rivero","year":"2013","journal-title":"J. Vet. Diagn. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/185909a0","article-title":"A hepatotoxin causing liver damage in facial eczema of sheep","volume":"185","author":"Worker","year":"1960","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"909","DOI":"10.2527\/1995.733909x","article-title":"Endogenous toxins and mycotoxins in forage grasses and their effects on livestock","volume":"73","author":"Cheeke","year":"1995","journal-title":"J. Anim. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1080\/00480169.2002.36263","article-title":"Mycotoxicoses of grazing animals in New Zealand","volume":"50","author":"Smith","year":"2002","journal-title":"N. Z. Vet. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1080\/00288230909510519","article-title":"A history of facial eczema (pithomycotoxicosis) research","volume":"52","author":"Smith","year":"2009","journal-title":"N. Z. J. Agric. Res."},{"key":"ref_8","first-page":"107","article-title":"First report of facial eczema in sheep in South Africa","volume":"39","author":"Marasas","year":"1972","journal-title":"Onderstepoort J. Vet. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1111\/j.1751-0813.1983.tb05937.x","article-title":"An abattoir survey of the prevalence of facial eczema in sheep in Western Australia","volume":"60","author":"Edwards","year":"1983","journal-title":"Aust. Vet. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.2460\/javma.1994.204.10.1668","article-title":"Photosensitization associated with exposure to Pithomyces chartarum in lambs","volume":"204","author":"Hansen","year":"1994","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_11","first-page":"339","article-title":"First identification of facial eczema in ewes in Europe","volume":"160","author":"Bezille","year":"1984","journal-title":"Recl. M\u00e9d. V\u00e9t."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1136\/vr.157.25.805","article-title":"Pithomycotoxicosis (facial eczema) in ruminants in the Azores, Portugal","volume":"157","author":"Pinto","year":"2005","journal-title":"Vet. Rec."},{"key":"ref_13","first-page":"858","article-title":"First case of pithomycotoxicosis (facial eczema) in the Netherlands","volume":"131","author":"Snoep","year":"2006","journal-title":"Tijdschr. Diergeneeskd."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s11250-008-9132-7","article-title":"Clinicopathological studies on facial eczema outbreak in sheep in Southwest Turkey","volume":"40","author":"Ozmen","year":"2008","journal-title":"Trop. Anim. Health Prod."},{"key":"ref_15","unstructured":"Ed Alabart, J.L., Alberti, P., Blasco, A., Garc\u00eda-Mar\u00edn, J.F., Manrique, E., and Purroy, A. (1991). Observaciones sobre el eczema facial de las ovejas. ITEA, Vol Extra, n\u00ba 11, Tomo, II, Editorial Alabart."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/0021-9975(74)90064-4","article-title":"Activity of gamma-glutamyl transpeptidase and other enzymes in the serum of sheep with liver or kidney damage","volume":"84","author":"Ford","year":"1974","journal-title":"J. Comp. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/0021-9975(83)90018-X","article-title":"Sporidesmin toxicity in rabbits: Biochemical and morphological changes","volume":"93","author":"Thompson","year":"1983","journal-title":"J. Comp. Pathol."},{"key":"ref_18","first-page":"13","article-title":"Clinical biochemistry of sporidesmin natural intoxication (facial eczema) of sheep","volume":"27","author":"Bonnefoi","year":"1989","journal-title":"J. Clin. Chem. Clin. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1080\/00480169.1978.34508","article-title":"Serum gamma-glutamyltransferase as a measure of sporidesmin-induced liver damage in sheep","volume":"26","author":"Towers","year":"1978","journal-title":"N. Z. Vet. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1080\/00480169.2000.36189","article-title":"Effects of low dose rates of sporidesmin administered orally to sheep","volume":"48","author":"Smith","year":"2000","journal-title":"N. Z. Vet. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1002\/jat.2550070306","article-title":"Pithomyces chartarum spore counts in rumen contents and faeces of sheep exposed to autumn pasture at three different grazing pressures","volume":"7","author":"Smith","year":"1987","journal-title":"J. Appl. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1016\/j.bbadis.2017.07.023","article-title":"Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium","volume":"1864","author":"Strazzabosco","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_23","first-page":"4076","article-title":"Immunohistochemical study for the origin of ductular reaction in chronic liver disease","volume":"7","author":"Lee","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1177\/0300985813513042","article-title":"Bile duct lesions associated with turnip (Brassica rapa) photosensitization compared with those due to sporidesmin toxicosis in dairy cows","volume":"51","author":"Collett","year":"2014","journal-title":"Vet. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.tox.2008.06.013","article-title":"Hepatic fibrosis-Overview","volume":"254","author":"Friedman","year":"2008","journal-title":"Toxicology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cld.2008.07.002","article-title":"Immune interactions in hepatic fibrosis or \u201cleucocyte-stromal interactions in hepatic fibrosis\u201d","volume":"12","author":"Holt","year":"2008","journal-title":"Clin. Liver Dis."},{"key":"ref_27","first-page":"511","article-title":"In vivo responses of macrophages and perisinusoidal cells to cholestatic liver injury","volume":"142","author":"Hines","year":"1993","journal-title":"Am. J. Pathol."},{"key":"ref_28","unstructured":"CES (2005). Metereolog\u00eda y climatolog\u00eda. Estado del Medio Ambiente en Asturias 2003, Consejo Econ\u00f3mico y Social (CES) del Principado de Asturias."},{"key":"ref_29","unstructured":"Aiello, S.E., Mays, A., Amstuz, H.E., Anderson, D.P., and Armour, J. (2000). El Manual Merck de Veterinaria, Oc\u00e9ano Grupo Editorial SA. [5th ed.]."},{"key":"ref_30","first-page":"231","article-title":"Photosensitivity in South Africa. II. The experimental production of the ovine hepatogenous photosensitivity disease geeldikkop (Tribulosis ovis) by the simultaneous ingestion of Tribulus terrestris plants and cultures of Pithomyces chartarum containing the mycotoxin sporidesmin","volume":"47","author":"Kellerman","year":"1980","journal-title":"Onderstepoort J. Vet. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1080\/00480169.2018.1515676","article-title":"Effects of sporidesmin on cultured biliary tract cells from Romney lambs that differed in their sensitivity to sporidesmin","volume":"66","author":"Lindsay","year":"2018","journal-title":"N. Z. Vet. J."},{"key":"ref_32","first-page":"571","article-title":"Ultrastructural changes in the isolated rat kidney induced by conjugated bilirubin and bile acids","volume":"57","author":"Gollan","year":"1976","journal-title":"Br. J. Exp. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/ki.2013.78","article-title":"Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction","volume":"84","author":"Salem","year":"2013","journal-title":"Kidney Int."},{"key":"ref_34","unstructured":"Maxie, M.G. (2016). Liver and biliary system. Jubb, Kennedy, and Palmer\u2019s Pathology of Domestic Animals, Elsevier. [6th ed.]."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/S1607-551X(09)70107-X","article-title":"Biliary cystadenocarcinoma associated with atrophy of the left hepatic lobe and hepatolithiasis mimicking intrahepatic cholangiocarcinoma: A case report","volume":"20","author":"Tseng","year":"2004","journal-title":"Kaohsiung J. Med. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1476-5926-7-5","article-title":"Relation between lipogranuloma formation and fibrosis, and the origin of brown pigments in lipogranuloma of the canine liver","volume":"7","author":"Isobe","year":"2008","journal-title":"Comp. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/jat.2550050206","article-title":"Studies on the mechanism of toxicity of the mycotoxin sporidesmin. IV Inhibition by copper-chelating agents of the generation of superoxide radical by sporidesmin","volume":"5","author":"Munday","year":"1985","journal-title":"J. Appl. Toxicol."},{"key":"ref_38","first-page":"436","article-title":"Useful algorithms for histopathological diagnosis of liver disease based on patterns of liver damage","volume":"31","year":"2016","journal-title":"Rev. Colomb. Gastroenterol."},{"key":"ref_39","first-page":"518","article-title":"Biliary tract anatomy and its relationship with venous drainage","volume":"4","author":"Babu","year":"2014","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1002\/jcb.24424","article-title":"Tumor necrosis factor-\u03b1 promotes bile ductular transdifferentiation of mature rat hepatocytes in vitro","volume":"114","author":"Nishikawa","year":"2013","journal-title":"J. Cell. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1002\/hep.30150","article-title":"Ductular reaction in liver diseases: Pathological mechanisms and translational significances","volume":"69","author":"Sato","year":"2019","journal-title":"Hepatology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.7150\/ijbs.20240","article-title":"Mesenchymal stem cell-dependent modulation of liver diseases","volume":"13","author":"Gazdic","year":"2017","journal-title":"Int. J. Biol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"357","DOI":"10.3389\/fonc.2018.00357","article-title":"Transforming growth factor-\u03b2-induced cell plasticity in liver fibrosis and hepatocarcinogenesis","volume":"8","author":"Fabregat","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1155\/1998\/192975","article-title":"Comparative quantitative analysis of macrophage populations defined by CD68 and carbohydrate antigens in normal and pathologically altered human liver tissue","volume":"16","author":"Baldus","year":"1998","journal-title":"Anal. Cell. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"430","DOI":"10.3389\/fimmu.2014.00430","article-title":"Hepatic localization of macrophage phenotypes during fibrogenesis and resolution of fibrosis in mice and humans","volume":"5","author":"Beljaars","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1164\/ajrccm\/140.4.1126","article-title":"Regulation of endothelial cell growth, architecture, and matrix synthesis by TGF-beta","volume":"140","author":"Roberts","year":"1989","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/labinvest.2011.7","article-title":"Arterial pathology in canine mucopolysaccharidosis-I and response therapy","volume":"91","author":"Lyons","year":"2011","journal-title":"Lab. Investig."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7165","DOI":"10.3748\/wjg.v21.i23.7165","article-title":"Activated rat hepatic stellate cells influence Th1\/Th2 profile in vitro","volume":"21","author":"Xing","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.tox.2016.12.009","article-title":"Lymphocytes contribute to biliary injury and fibrosis in experimental xenobiotic-induced cholestasis","volume":"377","author":"Joshi","year":"2017","journal-title":"Toxicology"},{"key":"ref_50","first-page":"2529","article-title":"Anatomical distribution of the hepatic artery in sheep","volume":"SP1","author":"Venkatesh","year":"2018","journal-title":"J. Pharmacogn. Phytochem."}],"container-title":["Animals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2615\/11\/4\/1070\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:26:39Z","timestamp":1760361999000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2615\/11\/4\/1070"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,9]]},"references-count":50,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ani11041070"],"URL":"https:\/\/doi.org\/10.3390\/ani11041070","relation":{},"ISSN":["2076-2615"],"issn-type":[{"value":"2076-2615","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,9]]}}}