Also, most studies were relatively under-powered and did not meet or publish CONSORT criteria for clinical trials. Despite these limitations, it can be summarized that (1) the use of vitamin E is associated with a decrease in aminotransferases in subjects with NASH, (2) studies where histologic endpoints were evaluated indicate that vitamin E causes improvement in steatosis, inflammation, and ballooning and resolution of steatohepatitis in adults with NASH, and (3) vitamin E has no effect on hepatic fibrosis. Although two meta-analyses8,

129 failed to observe significant histological benefits with vitamin E in patients with NASH, these analyses were conducted before PIVENS122 and TONIC130 trials were published. In the largest clinical trial (PIVENS)122 reported to date, the pure form of rrr α-tocopherol was orally administered at a dose of 800 IU/day for 96 weeks. The primary endpoint as stated previously was achieved in a significantly greater number of participants receiving vitamin E compared to placebo (42% vs. 19%, P< 0.001, number needed to treat= 4.4). One concern with vitamin E is the controversial issue of whether it increases all-cause mortality. Some meta-analyses have reported an increase in all-cause mortality with high dose vitamin E,131, 132 but others failed to confirm such an association.133-135 A recently published RCT showed that vitamin E administered at a dose of 400 IU/day

increased the risk of prostate cancer in relatively healthy men (absolute increase of 1.6 per 1000 person years of vitamin E use).136 Recommendation 21. Vitamin E (α-tocopherol) administered at daily dose of 800 IU/day improves liver histology in non-diabetic adults with biopsy-proven NASH and therefore it should be considered as a first-line pharmacotherapy for this patient population. (Strength -1, Quality – B) 22. Until further data supporting its effectiveness become available, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without most liver biopsy,

NASH cirrhosis, or cryptogenic cirrhosis (Strength – 1, Quality – C) Several studies126, 137-140 investigated UDCA (conventional and high doses) to improve aminotransferases and steatosis in patients with NAFLD and liver histology in patients with NASH. All but one study139 have been proof-of-concept studies with small numbers of participants and/or surrogate endpoints. Notably, a single large multicenter RCT convincingly showed that UDCA offers no histological benefit over placebo in patients with NASH.139 Omega-3 fatty acids, currently approved in the United States to treat hypertriglyceridemia, have been investigated to treat NAFLD both in animal models and in humans.141 A recent review by Masterton et al.,142 of published literature GW-572016 related to omega-3 fatty acids in NAFLD, found experimental evidence to support their use but the interpretation of human studies was limited by small sample size and methodological flaws.