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Vitamin E for Fatty Liver in AASLD Guidelines
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VITAMIN E
Oxidative stress is considered a key mechanism of hepatocellular injury and disease progression in subjects with NASH. Vitamin E is an antioxidant and has been investigated as a treatment for NASH.178-182 Comparison between these trials is difficult because of varying criteria for entry into the study, different doses of vitamin E, and unclear formulations of vitamin E used that could affect its bioavailability, the additional use of other antioxidants or other drugs, and limited histological data to assess outcomes. Also, most studies were relatively underpowered and did not meet or publish Consolidated Standards of Reporting Trials (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 in which histological endpoints were evaluated indicate that vitamin E results in improvement in steatosis, inflammation, and ballooning and resolution of SH in a proportion of nondiabetic adults with NASH, and (3) vitamin E did not have an effect on HF. In the PIVENS clinical trial,167 the pure form of rrr α‐tocopherol was orally administered at a dose of 800 IU/day for 96 weeks. The primary endpoint 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). In the Treatment of Nonalcoholic Fatty Liver Disease in Children trial (TONIC), which tested vitamin E (800 IU/day) or metformin (500 mg twice‐daily) against placebo in children with biopsy‐proven NAFLD, resolution of NASH was significantly greater in children treated with vitamin E than in children treated with placebo (58% vs. 28%; P = 0.006).183 Two recent meta‐analyses reported significant histological benefits with vitamin E in patients with NASH.184, 185
There are also lingering concerns about the long‐term safety of vitamin E. One meta‐analysis suggested that doses of >800 IU/day were associated with increased all‐cause mortality.186 However, this meta‐analysis has been criticized because several studies with low mortality were excluded and concomitant vitamin A and other drug administration as well as common factors, such as smoking, were not considered. A subsequent analysis of these trials with the addition of more studies suggested that the differences were driven by imbalance in males in the trials in question.187 A large meta‐analysis that included 57 studies and 246,371 subjects followed from 1 to 10 years did not demonstrate a relationship between vitamin E supplementation and all‐cause mortality.188 In a large RCT published in 2011, vitamin E administered at a dose of 400 IU/day was unexpectedly and unexplainably associated with a modest increase in the risk of prostate cancer (absolute increase of 1.6 per 1,000 person‐years of vitamin E use),189 and this risk may be modified by baseline selenium concentration190 or genetic variants associated with vitamin metabolism.191
Guidance Statements:
27. Vitamin E (rrr α‐tocopherol) administered at a daily dose of 800 IU/day improves liver histology in nondiabetic adults with biopsy‐proven NASH and therefore may be considered for this patient population. Risks and benefits should be discussed with each patient before starting therapy.
28. Until further data supporting its effectiveness become available, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis.
BARIATRIC SURGERY
NAFLD at all stages is more common in those who meet criteria for bariatric surgery. Nonsurgical weight loss is effective in improving all histological features of NAFLD, including fibrosis, though most patients had early‐stage fibrosis.136 However, sustained weight loss is difficult to achieve and harder yet to sustain. Bariatric surgery improves or eliminates comorbid disease in most patients and improves long‐term survival and death from CVD and malignancy, the two most common causes of death in NAFLD.192-195 Although there are no RCTs of bariatric surgery in NASH (and unlikely to be in the future), there are several retrospective and prospective cohort studies and two large, single‐center studies with follow‐up liver biopsies. Mathurin et al. prospectively correlated clinical and metabolic data with liver histology at time of surgery and 1 and 5 years after bariatric surgery in 381 adult patients with severe obesity.196 Gastric band, biliointestinal bypass, and gastric bypass were done in 56%, 23%, and 21%, respectively. Compared to baseline, there was a significant improvement in the prevalence and severity of steatosis and ballooning at 1 and 5 years following bariatric surgery. In patients with probable or definite NASH at baseline (n = 99), there was a significant improvement in steatosis, ballooning, and NAS and resolution of probable or definite NASH at 1 and 5 years following bariatric surgery. Most histological benefits were evident at 1 year, with no differences in liver histology between 1 and 5 years following bariatric surgery. Intriguingly, a minor, but statistically significant, increase in mean fibrosis score was noted at 5 years after the bariatric surgery (from 0.27 ± 0.55 at baseline to 0.36 ± 0.59; P = 0.001). Despite this increase, at 5 years, 96% of patients exhibited fibrosis score ≤1 and 0.5% had bridging fibrosis, indicating that there is no clinically significant worsening in fibrosis that can be attributed directly to the procedure. In a follow‐up study focused on those with NASH at baseline undergoing bariatric surgery, Lassailly et al. prospectively examined 109 patients with NASH at the time of bariatric surgery and performed follow‐up biopsies 1 year later. Eighty‐five percent of patients had NASH resolution (95% CI, 75.8‐92.2). Importantly, in contrast to past data, fibrosis improved at 1 year after surgery in 33% of patients.197 Furthermore, a meta‐analysis of available data in 2015 also showed that the majority of patients undergoing bariatric surgery appear to improve or completely resolve the histopathological features of steatosis, inflammation, and ballooning. Fibrosis also improved by a weighted mean decrease by 11.9% in the incidence of fibrosis.198
The safety and efficacy of bariatric surgery in patients with NASH cirrhosis is not well established. An analysis performed from the Nationwide Inpatient Sample (1998‐2007) estimated perioperative mortality and inpatient hospital stays for patients undergoing bariatric surgery with and without cirrhosis. Compared to those without cirrhosis (0.3%; n = 670,095), mortality was higher in those with compensated cirrhosis (0.9%; n = 3,888) and much higher in those with decompensated cirrhosis (16.3%; n = 62).199 A recent systematic review of bariatric surgery in 122 patients with cirrhosis (97% Child's A cirrhosis) described 1.6% early and 2.45% late, surgery‐related mortality.200 Noteworthy is 0% mortality associated with surgery among 41 patients with cirrhosis who had sleeve gastrectomy.
Guidance Statements:
29. Foregut bariatric surgery can be considered in otherwise eligible obese individuals with NAFLD or NASH.
30. It is premature to consider foregut bariatric surgery as an established option to specifically treat NASH.
31. The type, safety, and efficacy of foregut bariatric surgery in otherwise eligible obese individuals with established cirrhosis attributed to NAFLD are not established. In otherwise eligible patients with compensated NASH or cryptogenic cirrhosis, foregut bariatric surgery may be considered on a case‐by‐case basis by an experienced bariatric surgery program.
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