{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T05:49:02Z","timestamp":1761630542668,"version":"3.38.0"},"reference-count":22,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1888,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,7]]},"abstract":"\n \n \n Corticosteroid therapy has shown some benefit in severe acute alcoholic hepatitis (AAH); however, this is limited by uncertainty in patient selection and variable clinical response. Theophylline has been shown to ameliorate impaired steroid sensitivity in chronic obstructive pulmonary disease by facilitating corticosteroid-induced silencing of proinflammatory genes. We aimed to explore the mechanistic basis of the variable response to corticosteroid therapy seen in patients with AAH and to address the extent to which theophylline can improve this response. The ability of dexamethasone to inhibit phytohemagglutinin-induced lymphocyte proliferation was assessed by 3H-thymidine incorporation in 12 severe AAH patients and age-matched and sex-matched controls. Steroid sensitivity was measured in terms of Imax, the maximum inhibition of proliferation. The effect of 10\u22125 M theophylline and, in survivors, change in Imax during recovery were observed. Lymphocyte steroid sensitivity was found to be significantly reduced in AAH compared with controls (Imax 67[\u00b14.5]% versus 95[\u00b12.3]%,<\/jats:bold>\n \n P\n <\/jats:bold>\n = 0.0002) and correlated with clinical markers of steroid responsiveness. In survivors, Imax increased in recovery. Theophylline 10\u22125 M significantly increased lymphocyte steroid sensitivity (Imax 86[\u00b16.6]% versus 67[\u00b15.0]%,<\/jats:bold>\n \n P\n <\/jats:bold>\n = 0.027).<\/jats:bold>\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion:<\/jats:title>\n \n Acute alcoholic hepatitis is associated with significant lymphocyte steroid insensitivity, which improves in recovery and can be ameliorated<\/jats:bold>\n \n ex vivo\n <\/jats:bold>\n by theophylline. This offers potential to rationalize corticosteroid prescribing in AAH and, furthermore, justifies investigation of this novel role for an existing pharmacological agent in this common and frequently fatal condition. (Hepatology 2010;)<\/jats:bold>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/hep.23666","type":"journal-article","created":{"date-parts":[[2010,3,15]],"date-time":"2010-03-15T18:33:36Z","timestamp":1268678016000},"page":"126-131","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":28,"title":["Theophylline Improves Steroid Sensitivity in Acute Alcoholic Hepatitis"],"prefix":"10.1097","volume":"52","author":[{"given":"Stuart F. W.","family":"Kendrick","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elsbeth","family":"Henderson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David E. J.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris P.","family":"Day","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"R1-14-20250312","doi-asserted-by":"crossref","first-page":"480487","DOI":"10.1016\/S0168-8278(01)00289-6","article-title":"Corticosteroids improve shortterm survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH.","volume":"36","author":"Mathurin","year":"2002","journal-title":"J Hepatol"},{"key":"R2-14-20250312","first-page":"707711","article-title":"Alcoholic liver disease: morphological manifestations. Review by an international group.","volume":"1","author":"Baptista","year":"1981","journal-title":"Lancet"},{"key":"R3-14-20250312","doi-asserted-by":"crossref","first-page":"917920","DOI":"10.7326\/0003-4819-112-12-917","article-title":"Increased plasma tumor necrosis factor in severe alcoholic hepatitis.","volume":"112","author":"Bird","year":"1990","journal-title":"Ann Intern Med"},{"key":"R4-14-20250312","first-page":"449453","article-title":"Elevated plasma interleukin6 and increased severity and mortality in alcoholic hepatitis.","volume":"84","author":"Sheron","year":"1991","journal-title":"Clin Exp Immunol"},{"key":"R5-14-20250312","first-page":"4146","article-title":"Circulating and tissue levels of the neutrophil chemotaxin interleukin8 are elevated in severe acute alcoholic hepatitis, and tissue levels correlate with neutrophil infiltration.","volume":"18","author":"Sheron","year":"1993","journal-title":"Hepatology"},{"key":"R6-14-20250312","doi-asserted-by":"crossref","first-page":"13631369","DOI":"10.1016\/j.hep.2003.09.038","article-title":"Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone.","volume":"38","author":"Mathurin","year":"2003","journal-title":"Hepatology"},{"key":"R7-14-20250312","doi-asserted-by":"crossref","first-page":"382388","DOI":"10.1136\/gut.45.3.382","article-title":"Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes.","volume":"45","author":"Hearing","year":"1999","journal-title":"Gut"},{"key":"R8-14-20250312","doi-asserted-by":"crossref","first-page":"731733","DOI":"10.1016\/S0140-6736(04)15650-X","article-title":"Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase.","volume":"363","author":"Barnes","year":"2004","journal-title":"Lancet"},{"key":"R9-14-20250312","doi-asserted-by":"crossref","first-page":"334339","DOI":"10.1513\/pats.200504-024SR","article-title":"Theophylline in chronic obstructive pulmonary disease: new horizons.","volume":"2","author":"Barnes","year":"2005","journal-title":"Proc Am Thorac Soc"},{"key":"R10-14-20250312","doi-asserted-by":"crossref","first-page":"685690","DOI":"10.7326\/0003-4819-110-9-685","article-title":"Methylprednisolone therapy in patients with severe alcoholic hepatitis: a randomized multicenter trial.","volume":"110","author":"Carithers","year":"1989","journal-title":"Ann Intern Med"},{"key":"R11-14-20250312","doi-asserted-by":"crossref","first-page":"430435","DOI":"10.1002\/hep.1840040313","article-title":"Prognostic value of ChildTurcotte criteria in medically treated cirrhosis.","volume":"4","author":"Christensen","year":"1984","journal-title":"Hepatology"},{"key":"R12-14-20250312","doi-asserted-by":"crossref","first-page":"353358","DOI":"10.1002\/hep.20503","article-title":"MELD accurately predicts mortality in patients with alcoholic hepatitis.","volume":"41","author":"Dunn","year":"2005","journal-title":"Hepatology"},{"key":"R13-14-20250312","doi-asserted-by":"crossref","first-page":"11741179","DOI":"10.1136\/gut.2004.050781","article-title":"Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score.","volume":"54","author":"Forrest","year":"2005","journal-title":"Gut"},{"key":"R14-14-20250312","doi-asserted-by":"crossref","first-page":"10161025","DOI":"10.1164\/ajrccm\/144.5.1016","article-title":"Glucocorticoid resistance in chronic asthma: glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro.","volume":"144","author":"Corrigan","year":"1991","journal-title":"Am Rev Respir Dis"},{"key":"R15-14-20250312","first-page":"821825","article-title":"Response to glucocorticoid treatment in rheumatoid arthritis: in vitro cell mediated immune assay predicts in vivo responses.","volume":"18","author":"Kirkham","year":"1991","journal-title":"J Rheumatol"},{"key":"R16-14-20250312","first-page":"12961297","article-title":"Recipient lymphocyte sensitivity to methylprednisolone affects cadaver kidney graft survival.","volume":"1","author":"Langhoff","year":"1986","journal-title":"Lancet"},{"key":"R17-14-20250312","doi-asserted-by":"crossref","first-page":"197203","DOI":"10.1002\/hep.20021","article-title":"Oxidative stress as a trigger for cellular immune responses in patients with alcoholic liver disease.","volume":"39","author":"Stewart","year":"2004","journal-title":"Hepatology"},{"key":"R18-14-20250312","first-page":"41494154","article-title":"Wide variation in lymphocyte steroid sensitivity among healthy human volunteers.","volume":"84","author":"Hearing","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"key":"R20-14-20250312","doi-asserted-by":"crossref","first-page":"G718G724","DOI":"10.1152\/ajpgi.90232.2008","article-title":"Enhanced PDE4B expression augments LPSinducible TNF expression in ethanolprimed monocytes: relevance to alcoholic liver disease.","volume":"295","author":"Gobejishvili","year":"2008","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R21-14-20250312","doi-asserted-by":"crossref","first-page":"11901195","DOI":"10.1001\/archinte.166.11.1190","article-title":"Coffee, cirrhosis, and transaminase enzymes.","volume":"166","author":"Klatsky","year":"2006","journal-title":"Arch Intern Med"},{"key":"R22-14-20250312","doi-asserted-by":"crossref","first-page":"16371648","DOI":"10.1053\/gast.2000.20189","article-title":"Pentoxifylline improves shortterm survival in severe acute alcoholic hepatitis: a doubleblind, placebocontrolled trial.","volume":"119","author":"Akriviadis","year":"2000","journal-title":"Gastroenterology"},{"key":"R23-14-20250312","doi-asserted-by":"crossref","first-page":"465470","DOI":"10.1016\/j.jhep.2007.10.010","article-title":"Early switch to pentoxifylline in patients with severe alcoholic hepatitis is inefficient in nonresponders to corticosteroids.","volume":"48","author":"Louvet","year":"2008","journal-title":"J Hepatol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.23666","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201007000-00014","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T11:03:29Z","timestamp":1741777409000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201007000-00014"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,7]]},"references-count":22,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2010]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.23666","relation":{},"ISSN":["0270-9139"],"issn-type":[{"type":"print","value":"0270-9139"}],"subject":[],"published":{"date-parts":[[2010,7]]}}}