To the Editor:

In a recent, interesting article, Musso et al.,1 reviewing reports of randomized controlled trials, comprehensively assessed the efficacy of proposed treatments for nonalcoholic fatty liver disease (NAFLD). The authors concluded that well-designed randomized controlled trials are needed to assess the efficacy of proposed treatments with respect to patient-oriented outcomes contributing to the burden of NAFLD, such as cardiovascular disease (CVD).1 Evidence that has accumulated in recent years supports a potential link between NAFLD and an increased risk of CVD,2, 3 and this has prompted me to add a suggestion to be taken into consideration when future trials are designed to improve treatment efficacy: the employment of a dual-functional agent to combat NAFLD and prevent CVD. For instance, as one of the most important lipid-soluble antioxidants for humans, vitamin E has shown promising results for the treatment of fatty liver diseases, as indicated by many clinical trial studies.4, 5 A recent, rigorous trial that was reported in the New England Journal of Medicine4 found that supplementation with the natural form of vitamin E, in comparison with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis, the most extreme form of NAFLD. Moreover, the beneficial effect of vitamin E on CVD risk is supported by strong epidemiological evidence.6 Therefore, it is rational to infer that vitamin E as a dual-functional agent may be able to treat NAFLD and decrease the risk of CVD, and future trials examining its clinical effects are encouraged.

In addition, because oxidative stress plays an important role in both fatty liver disease7, 8 and CVD, the antioxidant activity of vitamin E should be the principal mechanism for treating or preventing these diseases. Because high-dosage vitamin E supplements (≥400 IU/day) potentially increase the risk for all-cause mortality and should be avoided,9 I suggest a moderate dosage of vitamin E in combination with other antioxidants such as vitamin C, which enhances the regeneration of oxidized vitamin E.10 The superiority of vitamin E and vitamin C combination therapy over single supplementation has been reported for several oxidative stress–associated diseases. However, we have to overcome the difficulties brought by the introduction of another intervention in future trials.

In summary, because of the increased risk of CVD for patients with NAFLD, the use of a dual-functional agent for the treatment of NAFLD and the prevention of CVD may represent an attractive strategy for improving the treatment efficacy and should be taken into consideration when future trials in NAFLD are being designed.


  1. Top of page
  • 1
    Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. HEPATOLOGY 2010; 52: 79-104.
  • 2
    Targher G, Marra F, Marchesini G. Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon? Diabetologia 2008; 51: 1947-1953.
  • 3
    Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis 2007; 191: 235-240.
  • 4
    Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362: 1675-1685.
  • 5
    Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003; 98: 2485-2490.
  • 6
    Cordero Z, Drogan D, Weikert C, Boeing H. Vitamin E and risk of cardiovascular diseases: a review of epidemiologic and clinical trial studies. Crit Rev Food Sci Nutr 2010; 50: 420-440.
  • 7
    McClain CJ, Mokshagundam SP, Barve SS, Song Z, Hill DB, Chen T, et al. Mechanisms of non-alcoholic steatohepatitis. Alcohol 2004; 34: 67-79.
  • 8
    Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001; 120: 1183-1192.
  • 9
    Miller ER III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005; 142: 37-46.
  • 10
    Chan AC. Partners in defense, vitamin E and vitamin C. Can J Physiol Pharmacol 1993; 1: 25-31.

Liang Shen Ph.D.*, * Shandong Provincial Research Center for Bioinformatic Engineering and Techniques, Shandong University of Technology, Zibo, People's Republic of China.