{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T23:58:15Z","timestamp":1792195095047,"version":"4.4.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T00:00:00Z","timestamp":1733097600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T00:00:00Z","timestamp":1733097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Metab Brain Dis"],"DOI":"10.1007\/s11011-024-01437-1","type":"journal-article","created":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T05:44:50Z","timestamp":1733118290000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Down the road towards hepatic encephalopathy. Urea synthesis - the liver workhorse of nitrogen metabolism"],"prefix":"10.1007","volume":"40","author":[{"given":"Hendrik","family":"Vilstrup","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1115-8308","authenticated-orcid":false,"given":"Peter Lykke","family":"Eriksen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6440-2784","authenticated-orcid":false,"given":"Kristoffer","family":"Kj\u00e6rgaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"S\u00f8rensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8118-4643","authenticated-orcid":false,"given":"Karen Louise","family":"Thomsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Ott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,2]]},"reference":[{"key":"1437_CR1","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1097\/01.alc.0000125355.31808.dc","volume":"28","author":"NK Aagaard","year":"2004","unstructured":"Aagaard NK, Th\u00f8gersen T, Gr\u00f8fte T et al (2004) Alcohol acutely down-regulates urea synthesis in normal men. Alcohol Clin Exp Res 28:697\u2013701. https:\/\/doi.org\/10.1097\/01.alc.0000125355.31808.dc","journal-title":"Alcohol Clin Exp Res"},{"key":"1437_CR2","doi-asserted-by":"publisher","first-page":"G269","DOI":"10.1152\/ajpgi.00062.2011","volume":"301","author":"G Dam","year":"2011","unstructured":"Dam G, Keiding S, Munk OL et al (2011) Branched-chain amino acids increase arterial blood ammonia in spite of enhanced intrinsic muscle ammonia metabolism in patients with cirrhosis and healthy subjects. Am J Physiol Gastrointest Liver Physiol 301:G269\u2013277. https:\/\/doi.org\/10.1152\/ajpgi.00062.2011","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"1437_CR3","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1016\/j.jhep.2018.06.023","volume":"69","author":"F De Chiara","year":"2018","unstructured":"De Chiara F, Heeb\u00f8ll S, Marrone G et al (2018) Urea cycle dysregulation in non-alcoholic fatty liver disease. J Hepatol 69:905\u2013915. https:\/\/doi.org\/10.1016\/j.jhep.2018.06.023","journal-title":"J Hepatol"},{"key":"1437_CR4","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1016\/j.jhep.2023.03.042","volume":"79","author":"PL Eriksen","year":"2023","unstructured":"Eriksen PL, Djernes L, Vilstrup H, Ott P (2023) Clearance and production of ammonia quantified in humans by constant ammonia infusion - the effects of cirrhosis and ammonia-targeting treatments. J Hepatol 79:340\u2013348. https:\/\/doi.org\/10.1016\/j.jhep.2023.03.042","journal-title":"J Hepatol"},{"key":"1437_CR5","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/0026-0495(95)90243-0","volume":"44","author":"A Fabbri","year":"1995","unstructured":"Fabbri A, Bianchi GP, Brizi M et al (1995) Effects of beta-blockade on hepatic conversion of amino acid nitrogen and on urea synthesis in cirrhosis. Metabolism 44:899\u2013905. https:\/\/doi.org\/10.1016\/0026-0495(95)90243-0","journal-title":"Metabolism"},{"key":"1437_CR6","doi-asserted-by":"publisher","unstructured":"Glavind E, Aagaard NK, Gr\u00f8nb\u00e6k H et al (2016) Alcoholic hepatitis markedly decreases the\u00a0Capacity for Urea Synthesis. PloS One 11:e0158388. https:\/\/doi.org\/10.1371\/journal.pone.0158388","DOI":"10.1371\/journal.pone.0158388"},{"key":"1437_CR7","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/0261-5614(94)90099-x","volume":"13","author":"O Hamberg","year":"1994","unstructured":"Hamberg O, Vilstrup H (1994) Regulation of urea synthesis by glucose and glucagon in normal man. Clin Nutr 13:183\u2013191. https:\/\/doi.org\/10.1016\/0261-5614(94)90099-x","journal-title":"Clin Nutr Edinb Scotl"},{"key":"1437_CR8","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/0168-8278(92)90164-K","volume":"14","author":"O Hamberg","year":"1992","unstructured":"Hamberg O, Nielsen K, Vilstrup H (1992) Effects of an increase in protein intake on hepatic efficacy for urea synthesis in healthy subjects and in patients with cirrhosis. J Hepatol 14:237\u2013243.\u00a0https:\/\/doi.org\/10.1016\/0168-8278(92)90164-k","journal-title":"J Hepatol"},{"key":"1437_CR9","first-page":"339","volume":"101","author":"P Ivarsen","year":"2001","unstructured":"Ivarsen P, Greisen J, Vilstrup H (2001) Acute effects of moderate dehydration on the hepatic conversion of amino nitrogen into urea nitrogen in healthy men. Clin Sci\u00a0(Lond.)\u00a01979 101:339\u2013344","journal-title":"Clin Sci Lond Engl 1979"},{"key":"1437_CR10","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1016\/j.neuint.2007.01.009","volume":"50","author":"ML Johansen","year":"2007","unstructured":"Johansen ML, Bak LK, Schousboe A et al (2007) The metabolic role of isoleucine in detoxification of ammonia in cultured mouse neurons and astrocytes. Neurochem Int 50:1042\u20131051. https:\/\/doi.org\/10.1016\/j.neuint.2007.01.009","journal-title":"Neurochem Int"},{"key":"1437_CR11","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1111\/j.1478-3231.2005.01032.x","volume":"25","author":"S Keiding","year":"2005","unstructured":"Keiding S, Munk OL, Vilstrup H et al (2005) Hepatic microcirculation assessed by positron emission tomography of first-pass ammonia metabolism in porcine liver. Liver Int 25:171\u2013176. https:\/\/doi.org\/10.1111\/j.1478-3231.2005.01032.x","journal-title":"Liver Int off J Int Assoc Study Liver"},{"key":"1437_CR12","doi-asserted-by":"publisher","first-page":"G151","DOI":"10.1152\/ajpgi.00128.2020","volume":"319","author":"TL Laursen","year":"2020","unstructured":"Laursen TL, Sandahl TD, Kazankov K et al (2020) Early normalization of reduced urea synthesis capacity after direct-acting antiviral therapy in hepatitis C cirrhosis. Am J Physiol Gastrointest Liver Physiol 319:G151\u2013G156. https:\/\/doi.org\/10.1152\/ajpgi.00128.2020","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"1437_CR13","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/j.clinre.2019.01.001","volume":"43","author":"P Lykke Eriksen","year":"2019","unstructured":"Lykke Eriksen P, S\u00f8rensen M, Gr\u00f8nb\u00e6k H et al (2019) Non-alcoholic fatty liver disease causes dissociated changes in metabolic liver functions. Clin Res Hepatol Gastroenterol 43:551\u2013560. https:\/\/doi.org\/10.1016\/j.clinre.2019.01.001","journal-title":"Clin Res Hepatol Gastroenterol"},{"key":"1437_CR14","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1053\/jhep.1996.v23.pm0008621138","volume":"23","author":"G Marchesini","year":"1996","unstructured":"Marchesini G, Fabbri A, Bianchi G et al (1996) Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis.\u00a0Hepatology 23:1084\u20131092. https:\/\/doi.org\/10.1053\/jhep.1996.v23.pm0008621138","journal-title":"Hepatol Baltim Md"},{"key":"1437_CR15","doi-asserted-by":"publisher","first-page":"G474","DOI":"10.1152\/ajpgi.00136.2020","volume":"320","author":"ACD Mikkelsen","year":"2021","unstructured":"Mikkelsen ACD, Thomsen KL, Vilstrup H et al (2021) Potassium deficiency decreases the capacity for urea synthesis and markedly increases ammonia in rats. Am J Physiol Gastrointest Liver Physiol 320:G474\u2013G483. https:\/\/doi.org\/10.1152\/ajpgi.00136.2020","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"1437_CR16","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1515\/bchm2.1954.297.1.61","volume":"297","author":"D Muting","year":"1954","unstructured":"Muting D (1954) [Amino acid content of human urine]. Hoppe Seylers Z Physiol Chem 297:61\u201367","journal-title":"Hoppe Seylers Z Physiol Chem"},{"key":"1437_CR17","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/S0021-9258(18)77120-2","volume":"83","author":"IM Rabinowitch","year":"1929","unstructured":"Rabinowitch IM (1929) Biochemical findings in a rare case of acute yellow atrophy of the liver: with particular reference to the origin of urea in the body. J Biol Chem 83:333\u2013335. https:\/\/doi.org\/10.1016\/S0021-9258(18)77120-2","journal-title":"J Biol Chem"},{"key":"1437_CR18","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1016\/0016-5085(78)90851-X","volume":"75","author":"L Rikkers","year":"1978","unstructured":"Rikkers L, Jenko P, Rudman D, Freides D (1978) Subclinical hepatic encephalopathy: detection, prevalence, and relationship to nitrogen metabolism. Gastroenterology 75:462\u2013469","journal-title":"Gastroenterology"},{"key":"1437_CR19","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1111\/j.1478-3231.2010.02362.x","volume":"31","author":"TD Sandahl","year":"2011","unstructured":"Sandahl TD, Aagaard NK, Thomsen KL et al (2011) Effects of insulin-like growth factor-I administration on in vivo regulation of urea synthesis in normal subjects and patients with cirrhosis.\u00a0Liver Int\u00a031:132\u2013137. https:\/\/doi.org\/10.1111\/j.1478-3231.2010.02362.x","journal-title":"Liver Int off J Int Assoc Study Liver"},{"key":"1437_CR20","doi-asserted-by":"publisher","first-page":"151","DOI":"10.3109\/00365511003599537","volume":"70","author":"KL Thomsen","year":"2010","unstructured":"Thomsen KL, Nielsen SS, Aagaard NK et al (2010) Tumor necrosis factor-alpha acutely up-regulates urea synthesis in vivo in rats\u2013a hepatic component of inflammatory catabolism? Scand J Clin Lab Invest 70:151\u2013157. https:\/\/doi.org\/10.3109\/00365511003599537","journal-title":"Scand J Clin Lab Invest"},{"key":"1437_CR21","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1136\/gut.21.11.990","volume":"21","author":"H Vilstrup","year":"1980","unstructured":"Vilstrup H (1980) Synthesis of urea after stimulation with amino acids: relation to liver function. Gut 21:990\u2013995.\u00a0https:\/\/doi.org\/10.1136\/gut.21.11.990","journal-title":"Gut"},{"key":"1437_CR22","first-page":"415","volume":"36","author":"H Vilstrup","year":"1989","unstructured":"Vilstrup H (1989) On urea synthesis\u2013regulation in vivo. Dan Med Bull 36:415\u2013429","journal-title":"Dan Med Bull"},{"key":"1437_CR23","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1111\/j.1365-2362.1982.tb00993.x","volume":"12","author":"H Vilstrup","year":"1982","unstructured":"Vilstrup H, Bucher D, Krog B, Damg\u00e5rd SE (1982) Elimination of infused amino acids from plasma of control subjects and of patients with cirrhosis of the liver. Eur J Clin Invest 12:197\u2013202. https:\/\/doi.org\/10.1111\/j.1365-2362.1982.tb00993.x","journal-title":"Eur J Clin Invest"},{"key":"1437_CR24","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1111\/j.1365-2362.1986.tb01328.x","volume":"16","author":"H Vilstrup","year":"1986","unstructured":"Vilstrup H, Iversen J, Tygstrup N (1986) Glucoregulation in acute liver failure. Eur J Clin Invest 16:193\u2013197. https:\/\/doi.org\/10.1111\/j.1365-2362.1986.tb01328.x","journal-title":"Eur J Clin Invest"},{"key":"1437_CR25","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/0168-8278(90)90072-y","volume":"10","author":"H Vilstrup","year":"1990","unstructured":"Vilstrup H, Hansen BA, Almdal TP (1990) Glucagon increases hepatic efficacy for urea synthesis. J Hepatol 10:46\u201350. https:\/\/doi.org\/10.1016\/0168-8278(90)90072-y","journal-title":"J Hepatol"},{"key":"1437_CR26","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1002\/hep.27210","volume":"60","author":"H Vilstrup","year":"2014","unstructured":"Vilstrup H, Amodio P, Bajaj J et al (2014) Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the study of the liver.\u00a0Hepatology\u00a060:715\u2013735. https:\/\/doi.org\/10.1002\/hep.27210","journal-title":"Hepatol Baltim Md"},{"key":"1437_CR27","doi-asserted-by":"publisher","first-page":"101080","DOI":"10.1016\/j.molmet.2020.101080","volume":"42","author":"M Winther-S\u00f8rensen","year":"2020","unstructured":"Winther-S\u00f8rensen M, Galsgaard KD, Santos A et al (2020) Glucagon acutely regulates hepatic amino acid catabolism and the effect may be disturbed by steatosis. Mol Metab 42:101080. https:\/\/doi.org\/10.1016\/j.molmet.2020.101080","journal-title":"Mol Metab"},{"key":"1437_CR28","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1111\/j.1440-1681.1998.tb02284.x","volume":"25","author":"PC Withers","year":"1998","unstructured":"Withers PC (1998) Urea: diverse functions of a waste product. Clin Exp Pharmacol Physiol 25:722\u2013727","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"1437_CR29","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1016\/S0168-8278(97)80314-5","volume":"27","author":"T Wolthers","year":"1997","unstructured":"Wolthers T, Gr\u00f8fte T, J\u00f8rgensen JO, Vilstrup H (1997) Growth hormone prevents prednisolone-induced increase in functional hepatic nitrogen clearance in normal man. J Hepatol 27:789\u2013795.\u00a0https:\/\/doi.org\/10.1016\/s0168-8278(97)80314-5","journal-title":"J Hepatol"},{"key":"1437_CR30","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/S0168-8278(00)80006-9","volume":"33","author":"T Wolthers","year":"2000","unstructured":"Wolthers T, Hamberg O, Gr\u00f8fte T, Vilstrup H (2000) Effects of budesonide and prednisolone on hepatic kinetics for urea synthesis. J Hepatol 33:549\u2013554","journal-title":"J Hepatol"}],"container-title":["Metabolic Brain Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11011-024-01437-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11011-024-01437-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11011-024-01437-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:52:41Z","timestamp":1740531161000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11011-024-01437-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,2]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["1437"],"URL":"https:\/\/doi.org\/10.1007\/s11011-024-01437-1","relation":{},"ISSN":["1573-7365"],"issn-type":[{"value":"1573-7365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,2]]},"assertion":[{"value":"14 June 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 October 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 December 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"49"}}