{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:57:12Z","timestamp":1780102632117,"version":"3.54.0"},"reference-count":48,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2015,11,23]],"date-time":"2015-11-23T00:00:00Z","timestamp":1448236800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2015,11,23]],"date-time":"2015-11-23T00:00:00Z","timestamp":1448236800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2016,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alkaptonuria (AKU) is a rare inherited metabolic disorder of tyrosine metabolism that results from a defect in an enzyme called homogentisate 1,2\u2010dioxygenase. The result of this is that homogentisic acid (HGA) accumulates in the body. HGA is central to the pathophysiology of this disease and the consequences observed; these include spondyloarthropathy, rupture of ligaments\/muscle\/tendons, valvular heart disease including aortic stenosis and renal stones. While AKU is considered to be a chronic progressive disorder, it is clear from published case reports that fatal acute metabolic complications can also occur. These include oxidative haemolysis and methaemoglobinaemia. The exact mechanisms underlying the latter are not clear, but it is proposed that disordered metabolism within the red blood cell is responsible for favouring a pro\u2010oxidant environment that leads to the life threatening complications observed. Herein the role of red blood cell in maintaining the redox state of the body is reviewed in the context of AKU. In addition previously reported therapeutic strategies are discussed, specifically with respect to why reported treatments had little therapeutic effect. The potential use of nitisinone for the management of patients suffering from the acute metabolic decompensation in AKU is proposed as an alternative strategy.<\/jats:p>","DOI":"10.1007\/s10545-015-9902-0","type":"journal-article","created":{"date-parts":[[2015,11,23]],"date-time":"2015-11-23T13:41:29Z","timestamp":1448286089000},"page":"203-210","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Acute fatal metabolic complications in alkaptonuria"],"prefix":"10.1002","volume":"39","author":[{"given":"A. S.","family":"Davison","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories Royal Liverpool University Hospitals Trust Liverpool L7 8XP UK"},{"name":"Bone and Joint Research Group, Musculoskeletal Biology University of Liverpool Liverpool L69 3GA UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. M.","family":"Milan","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories Royal Liverpool University Hospitals Trust Liverpool L7 8XP UK"},{"name":"Bone and Joint Research Group, Musculoskeletal Biology University of Liverpool Liverpool L69 3GA UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. A.","family":"Gallagher","sequence":"additional","affiliation":[{"name":"Bone and Joint Research Group, Musculoskeletal Biology University of Liverpool Liverpool L69 3GA UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. R.","family":"Ranganath","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories Royal Liverpool University Hospitals Trust Liverpool L7 8XP UK"},{"name":"Bone and Joint Research Group, Musculoskeletal Biology University of Liverpool Liverpool L69 3GA UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,11,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320140115"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00648.x"},{"key":"e_1_2_10_4_1","first-page":"1","article-title":"Pathological roles of reactive oxygen species and their defence mechanisms","volume":"12","author":"Al\u2010Omar MA","year":"2004","journal-title":"Saudi Pharm J"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.5414\/CN108188"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V22.3.323.323"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","unstructured":"BraconiDMillucciLBernardiniGetalOxidative stress and mechanisms of ochronosis in alkaptonuriaFree Radic Biol Med2015.","DOI":"10.1016\/j.freeradbiomed.2015.02.021"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2007.12.025"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60073-2"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0891-5849(96)00233-X"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2014-0668"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.2011.04048.x"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/ckj\/sfs079"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.3109\/13813459409007534"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2009.11.023"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASN.0000138232.68452.3B"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1159\/000014380"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1096-7192(02)00121-X"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2011.04.016"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aes422"},{"key":"e_1_2_10_21_1","first-page":"441","article-title":"Alkaptonuria and renal failure: a case report","volume":"17","author":"Kazancioglu R","year":"2004","journal-title":"J Nephrol"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.5858\/2001-125-0961-DMIIOA"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2005.05.013"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-014-0107-7"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1517\/21678707.2013.800807"},{"key":"e_1_2_10_26_1","first-page":"76","article-title":"Studies of alcaptonuria: inheritance of 47 cases in eight highly inter\u2010related Dominican kindreds","volume":"12","author":"Milch RA","year":"1960","journal-title":"Am J Hum Genet"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2012.07.011"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-015-9842-8"},{"key":"e_1_2_10_29_1","first-page":"112","article-title":"An autopsy case of methemoglobinemia with ochronosis. 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