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To the Editor:

We read with great interest the recent article by Kugelmas et al.,1 reporting plasma cytokine levels in patients with NASH and the effect of diet and vitamin E on this disease. They found that plasma tumor necrosis factor (TNF), interleukin 8, and interleukin 6 concentrations were significantly elevated compared with control values, and only plasma interleukin 6 levels significantly decreased with diet therapy. This article further reported that vitamin E therapy did not independently influence the biochemical data and plasma cytokine levels in patients with NASH. We previously investigated the plasma transforming growth factor-β1 (TGF-β1) level and the efficacy of vitamin E in patients with NASH.2 We enrolled 12 patients with NASH and 10 with fatty liver. All patients were given dietary instruction for 6 months, and thereafter vitamin E (α-tocopherol acetate, Juvera™, Eisai Pharmaceutical Co., Tokyo, Japan, 300 mg/day; 100 mg is equivalent to 100 IU) was given for 1 year. In consequence, the plasma TGF-β1 level in patients with NASH (37 ± 5 ng/ml) was significantly higher than that in patients with fatty liver (10 ± 4 ng/ml) and healthy subjects (9 ± 5 ng/ml). Moreover, this elevated plasma TGF-β1 level decreased after a 1-year vitamin E treatment, together with the improvement of biochemical markers and hepatic pathological findings (Table 1). In 5 out of 9 NSAH patients in whom liver biopsy was performed after vitamin E treatment, inflammation and fibrosis were improved. On the other hand, diet therapy improved biochemical data only in patients with fatty liver, but not in those with NASH. We conducted our previous study to assess the efficacy of a long-term vitamin E treatment (a 1-year vitamin E administration after a 6-month diet). However, in the studies performed by Kugelmas et al.,1 vitamin E was given for only 12 weeks and the patients were given diet therapy at the same time. In fact, Kugelmas et al.1 mentioned that longer study duration might have shown the efficacy of vitamin E on NASH. However, we had already reported the efficacy of a 12-month treatment of vitamin E on NASH. Moreover, long-term treatment with vitamin E for patients with NASH was tried for obese children and Japanese adults, and the beneficial effect of this vitamin has already been confirmed.3, 4 In addition, the NIH plans to conduct randomized controlled trials of insulin-sensitizing agents and vitamin E therapy for NASH.5 Although the role of tumor necrosis factor is currently debated in the literature,6, 7 elevated blood level of TGF-β has recently been ascertained.8 The role of TGF-β1 in hepatic inflammation and fibrosis has been well documented in both animal and clinical studies.9, 10 Therefore, for better understanding of the cytokine network in NASH, we believe that the investigation of plasma TGF-β1 is essential, as well as long-term observation of vitamin E treatment.

Table 1. Effect of Vitamin E on Serum Alanine Transaminase (ALT) and Plasma TGF-β1 Levels in Patients With NASH
 Before TreatmentAfter DietAfter Vitamin E
  1. Modified from Hasegawa et al.2

ALT (IU/L)171 ± 4161 ± 1437 ± 4
TGF-β1 (ng/ml)37 ± 536 ± 69 ± 6

References

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  • 1
    Kugelmas M, Hill DB, Vivian B, Marsano L, McClain C. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. HEPATOLOGY 2003; 38: 413419.
  • 2
    Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A. Plasma transforming growth factor-β1 level and efficacy of α-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 2001; 15: 16671672.
  • 3
    Lavine, JE. Vitamine E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr 2000; 136: 734738.
  • 4
    Kawanaka M, Mahomood S, Niiyama G, Izumi A, Kamei A, Ikeda H, Suehiro M, et al. A pilot study of vitamin E treatment in patients with nonalcoholic steatohepatitis: control of oxidative stress and reduction in biochemical markers. Hepatol Res (In press).
  • 5
    Anonymous. Nonalcoholic steatohepatitis clinical research network. HEPATOLOGY 2003; 37: 244.
  • 6
    Tilg H, Diehl AM. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Eng J Med 2000; 20: 14671476.
  • 7
    Valenti L, Fracanzani AL, Dongiovanni P, Santorelli G, Branchi A, Taioli E, Feorelli G, et al. Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology 2002; 122: 274280.
  • 8
    Perrella A, Tarantino G, Borgia G, Conca P, Sorrentino P, Ragucci P, Vecchione R, et al. Cytokine network during NASH and possible treatment selection. HEPATOLOGY 2003; 38: 530.
  • 9
    De Bleser P, Niki T, Rogiers V, Geerts A. Transforming growth factor-β gene expression in normal and fibrotic rat liver. J Hepatol 1997; 26: 886893.
  • 10
    Nelson DR, Gonzalez PR, Qian K, Xu Y, Marousis CG, Davis GL, Lau JY. Transforming growth factor-β1 in chronic hepatitis C. J Viral Hepat 1997; 4: 2935.