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Vitamin E improves histology of NASH, patient-oriented benefit unknown

Clinical Question:
Are vitamin E or piogliazone effective for the treatment of nonalcoholic steatohepatitis?

Bottom Line:
These findings will be touted as proof that vitamin E, and possibly pioglitazone (Actos), are effective treatments for nonalcoholic steatohepatitis. However, the danger of this condition is often overstated. Although the introduction to this study notes that up to 15% of patients progress to cirrhosis, this is in highly selected referral populations. The true incidence is much lower, as shown by progression of only 1 of 247 patients over the 2 years of this study. The histologic and biochemical "benefit" of vitamin E and pioglitazone must be balanced against the known harms of these drugs. For example, a previous meta-analysis found an excess of 1 death for every 300 patients randomized to receive vitamin E (Ann Intern Med 2005; 142:37-46; POEM 70254). (LOE = 1b)

Reference:
Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362(18):1675-1685.  [PMID:20427778]

Study Design:
Randomized controlled trial (double-blinded)

Funding:
Industry + govt

Allocation:
Uncertain

Setting:
Outpatient (any)

Synopsis:
Steatohepatitis is a "predisease" that in a minority of patients leads to cirrhosis. Vitamin E and thiazolidinediones like pioglitazone have been recommended as potential treatments, but have not been evaluated in randomized controlled trials. This trial enrolled 247 nondiabetic adults with possible or definite steatohepatitis based on liver biopsy and less than 20 g per day of alcohol use for women and 30 g for men. Their mean age was 46 years and 60% were female. All had moderate severity of disease or worse, defined as a disease activity score of 5 or greater (if steatohepatitis was possible) and 4 or greater (if definite), on a scale of 0 to 8 points. Persons with cirrhosis, taking medications known to cause liver damage, or with hepatitis were excluded.They were then randomized (allocation concealment unknown) to receive either vitamin E 800 IU, pioglitazone 30 mg, or matching placebo, each given once daily. After slightly less than 2 years of follow-up, patients underwent a second liver biopsy. The primary outcome was histologic improvement in the disease activity, measured by the degree of hepatocellular ballooning, fibrosis, inflammation, and steatosis. Improvement in histologic disease severity was greater in the vitamin E group than in the placebo group (43% vs 19%; P = .001; number needed to treat = 4.2), but not for pioglitazone. The hepatic aminotransferase levels decreased in the active treatment groups but then reverted to the same level as in placebo patients after the drugs were discontinued. Regarding patient-oriented outcomes, there was no difference in quality of life, and patients in the pioglitazone group gained approximately 2.5 kg. Only a single patient progressed to cirrhosis during the study, from the vitamin E group.

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