We appreciate the comments of Yoneda and coworkers and Vajro and coworkers. Over 15 years ago, our laboratory first described elevated serum IL-1 levels in alcoholic hepatitis patients, and subsequently we reported increased monocyte production of tumor necrosis factor alpha in these patients.1, 2 It is now well documented that dysregulated cytokine metabolism plays a pivotal role in the development of liver injury and many of the metabolic/systemic complications of alcoholic hepatitis.3–5 The major goal of our study in nonalcoholic steatohepatitis (NASH) patients was to determine whether they had similarly elevated serum concentrations of proinflammatory/acute-phase cytokines and increased monocyte production of these cytokines.6 Next, we wanted to determine whether these patients had increased serum hyaluronic acid levels, a marker of sinusoidal endothelial cell dysfunction and fibrosis. Lastly, we wanted to determine the possible beneficial effects of short-term weight loss and vitamin E supplementation.
Hasegawa, Yoneda, and coworkers report their findings on vitamin E supplementation on transforming growth factor beta (TGF-β) levels in NASH patients.7 We certainly agree that TGF-β is an important profibrotic cytokine that requires further evaluation in NASH patients. It is also clear in in vitro and in animal studies that vitamin E is highly effective at blocking activation of stellate cells and fibrosis and blocking inflammation and liver injury.8, 9 However, the efficacy of vitamin E in humans in a variety of inflammatory states has been much more controversial. A classic example is the multiple cardiovascular studies in which vitamin E alone or in combination with other antioxidants has been extensively evaluated. There are a host of atherosclerosis studies with “alphabet soup” names such as HOPE, CHAOS, etc., that have yielded conflicting data, with most of the larger studies finding limited or no beneficial effects of vitamin supplementation.10 A major issue is whether the vitamin E dose administered has been appropriate. If one is trying to decrease oxidative stress then vitamin E should be given in a dose sufficient to decrease oxidative stress, as assessed by markers such as urinary isoprostanes, or to reduce activation of redox sensitive transcription factors such as nuclear factor-κB (NFκB).10 Thus, our strong opinion is that appropriate antioxidant-dose-finding studies need to be performed before large clinical trials are initiated. Reviewing the study by Hasegawa, Yoneda, and coworkers, one could argue that NASH patients improved their TGF-β levels merely as a beneficial effect of diet and weight loss, and the effect was not seen immediately, but only after a one-year period of time that included vitamin E therapy. Their study was neither randomized nor placebo-controlled, and it would be very premature to say that 300 IU of vitamin E is appropriate therapy for NASH or for downregulating TGF-β levels. There also could be racial/ethnic differences in how Japanese respond to vitamin E therapy versus Americans.
We also agree with Varjro and coworkers that compliance is always an issue in clinical studies. We did not measure vitamin E levels in our patients. However, pill counts were performed, and all patients had over 80% compliance. Moreover, patients were contacted by telephone on a weekly basis and seen in clinic every three to six weeks. The study was performed as part of a master's degree thesis (Beverly Vivian), and was done on a National Institutes of Health–funded General Clinical Research Center. Thus, adherence to both diet and exercise, and medication compliance would be much more likely in this study than in standard medical practice, in our opinion. We agree with both investigators that antioxidants have great theoretic potential in NASH. However, we feel that it is important to scientifically determine the appropriate dose of vitamin E and whether vitamin E should potentially be given with other antioxidants such as glutathione prodrugs to achieve maximal benefit.