UNLABELLED: 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 (3)H-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.
UNLABELLED: 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 (3)H-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.
Authors: Ashwani K Singal; Sudha Kodali; Lee A Vucovich; Victor Darley-Usmar; Thomas D Schiano Journal: Alcohol Clin Exp Res Date: 2016-06-02 Impact factor: 3.455