Theophylline improves steroid sensitivity in acute alcoholic hepatitis, according to the results of a new study conducted in Newcastle upon Tyne, UK.

Acute alcoholic hepatitis is characterized by inflammation and high levels of circulating proinflammatory cytokines. However, patients with this disease have variable responses to steroid therapy; an early fall in serum bilirubin level indicates responsiveness to therapy, whereas there is no benefit of such therapy in patients whose serum bilirubin levels do not fall by the seventh day of treatment.

Stuart Kendrick and colleagues hypothesized that theophylline might improve steroid sensitivity in patients with acute alcoholic hepatitis. “Our inspiration came from two sources,” explains Kendrick, lead author of the study. “First was research on steroid sensitivity in ulcerative colitis, which demonstrated that an assay of the responsiveness of peripheral blood mononuclear cells was a good correlate of clinical steroid responsiveness. Second was work in chronic obstructive pulmonary disease, which showed that the oxidative stress associated with cigarette smoking impaired the ability of the activated glucocorticoid receptor to switch off the transcription of inflammatory genes. However, theophylline could overcome this inhibition by improving the ability of the glucocorticoid receptor to recruit histone deacetylases, which are key mediators of transcriptional silencing.”

Kendrick et al. enroled 12 patients with acute alcoholic hepatitis and 12 age-matched and sex-matched controls. Patients received prednisolone 40 mg daily for 28 days. Steroid sensitivity was measured by the ability of dexamethasone to inhibit phytohemagglutinin-induced lymphocyte proliferation—measured in terms of the maximum inhibition of proliferation. Lymphocyte steroid sensitivity was assessed at baseline and every 4 weeks for 6 months in surviving patients who attended follow-up. The same assay was conducted in the presence of theophylline in the patients' baseline blood samples.

Steroid sensitivity was found to be significantly reduced in patients with severe alcoholic hepatitis compared with age-matched and sex-matched controls. Furthermore, within the group of patients with acute alcoholic hepatitis, steroid sensitivity at presentation was greater in those patients who went on to show a fall in serum bilirubin levels by the seventh day of treatment compared with those who did not, which suggests that in vitro steroid sensitivity correlates with clinical steroid responsiveness.

“Adding theophylline improved ex vivo steroid sensitivity, suggesting that theophylline might have potential to improve response in steroid-treated alcoholic hepatitis,” says Kendrick. “As 16% of patients die even with steroid therapy, this could be a useful new observation.”

The authors believe that their findings underline the importance of investigating the role of this existing pharmacological agent in acute alcoholic hepatitis. “We plan to go on with a clinical trial to see if oral theophylline improves the rate of early change in serum bilirubin level,” concludes Kendrick. “If this is promising, a larger trial assessing the outcomes and cost-effectiveness of theophylline could be conducted.”