Theophylline Improves Steroid Sensitivity in Acute Alcoholic Hepatitis

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 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 25 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[64.5]% versus 95[62.3]%, P 5 0.0002) and correlated with clinical markers of steroid responsiveness. In survivors, I max increased in recovery. Theophylline 10 25 M significantly increased lymphocyte steroid sensitivity (I max 86[66.6]% versus 67[65.0]%, P 5 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)

Genome of the Chinese tree shrew

“…A total of 42 genes are known targets for hepatitis drugs, such as halothane, theophylline and meperidine 50,51 . Only one gene, neuropeptide S receptor 1 (NPSR1), has lost its targeted domain (7tm-1) of halothane in tree shrews owing to the frame-shift mutation ( Supplementary Fig.…”

Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets

“…124 The decision to stop corticosteroids can be based on calculation of the Lille Model after 7 days of treatment; a Lille Model score greater than 0.45 indicates failure to respond to corticosteroid treatment and predicts a 6-month survival rate of less than 25%. 125 Severe acute AH is associated with significant lymphocyte corticosteroid insensitivity, which can be reduced ex vivo by theophylline administration 126 or reagents that block the IL-2 receptor. 127 These drugs might therefore improve the efficacy of corticosteroids in treating AH.…”

Diagnosis and Treatment of Alcoholic Hepatitis: A Systematic Review

“…(Richardet JP, 1993, Spahr et al, 2001) However, response is observed in only 40–50% patients, whose lymphocytes are sensitive to inhibition of proliferation with corticosteroids. (Kendrick et al, 2010) Further, corticosteroids have potential side effects of such as infections, hyperglycemia, electrolyte disturbance, and weight gain. Of these, infection, especially fungal infections, is most relevant in AH patients.…”