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Theophylline improves steroid sensitivity in acute alcoholic hepatitis

Lookup NU author(s): Dr Stuart Kendrick, Elsbeth Henderson, Dr Jeremy Palmer, Professor David Jones, Professor Chris Day

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Abstract

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 H-3-thymidine incorporation in 12 severe AAH patients and age-matched and sex-matched controls. Steroid sensitivity was measured in terms of I-max, the maximum inhibition of proliferation. The effect of 10(-5) M theophylline and, in survivors, change in I-max during recovery were observed. Lymphocyte steroid sensitivity was found to be significantly reduced in AAH compared with controls (I-max 67[+/- 4.5]% versus 95[+/- 2.3]%, P = 0.0002) and correlated with clinical markers of steroid responsiveness. In survivors, I-max increased in recovery. Theophylline 10(-5) M significantly increased lymphocyte steroid sensitivity (I-max 86[+/- 6.6]% versus 67[+/- 5.0]%, P = 0.027). Conclusion: Acute alcoholic hepatitis is associated with significant lymphocyte steroid insensitivity, which improves in recovery and can be ameliorated ex vivo 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;52:126-131)


Publication metadata

Author(s): Kendrick SFW, Henderson E, Palmer J, Jones DEJ, Day CP

Publication type: Article

Publication status: Published

Journal: Hepatology

Year: 2010

Volume: 52

Issue: 1

Pages: 126-131

Print publication date: 15/03/2010

ISSN (print): 0270-9139

ISSN (electronic): 1527-3350

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1002/hep.23666

DOI: 10.1002/hep.23666


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