Vitamin E Improves Transplant‐free Survival and Hepatic Decompensation among Patients with NASH and Advanced Fibrosis

Vitamin E improves liver histology in non-diabetic adults with nonalcoholic steatohepatitis (NASH), but its impact on long-term patient outcomes is unknown. We evaluated whether vitamin E treatment improves clinical outcomes of NASH patients with bridging fibrosis or cirrhosis. Two hundred and thirty-six patients with biopsy-proven NASH and bridging fibrosis or cirrhosis seen at Indiana University Medical Center between October 2004, and January 2016 were included. Ninety of them took 800 IU/day of vitamin E for ≥ 2 years (vitamin E users) and were propensity matched to 90 adults who did not take vitamin E (controls) after adjusting for fibrosis severity, age, gender, body mass index, comorbidities and their treatment, LDL cholesterol, liver biochemistries and length of follow-up on vitamin E. Covariate-adjusted cox and competing risk regression models were assessed to evaluate association between vitamin E treatment and patient outcomes. The median follow-up was 5.62 (IQR: 4.3-7.5) and 5.6 (IQR: 4-6.9) years for vitamin E users and controls respectively. A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. Vitamin E users had higher adjusted transplant-free survival (78% vs. 49%, P<.01) and lower rates of hepatic decompensation (37% vs. 62%, P=.04) than controls. After controlling for severity of fibrosis, calendar year of patient enrollment and other potential confounders, vitamin E treatment decreased the risk of death or transplant (adj. HR: 0.30, 95% CI: 0.120.74, P<.01) and hepatic decompensation (adj. sHR: 0.52, 95% CI: 0.28-0.96, P=.036). These benefits were evident in both diabetics as well as non-diabetics. Adjusted 10-year cumulative probability of HCC, vascular events and non-hepatic cancers were not different between vitamin E exposed and controls. Conclusion, vitamin E use was associated with improved clinical outcomes in patients with NASH and bridging fibrosis or cirrhosis. Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease and hepatocellular carcinoma (HCC), and recently has become a leading indication for liver transplantation in the industrialized countries. (1) The prevalence of NAFLD varies across the different countries, being from 20-30% in Europe and as high as 46% in the United States (U.S). (2, 3) The prevalence of NAFLD can also be higher in obese subjects and among patients with type 2 diabetes (T2D). Approximately 25% patients with NAFLD may progress to nonalcoholic steatohepatitis (NASH), and 11% of NASH patients may developed cirrhosis within 15 years. (4) The prognosis of NAFLD is determined by the severity of hepatic fibrosis; patients with bridging fibrosis or cirrhosis carry a higher risk of hepatic decompensation secondary to portal hypertension, HCC and death as compared with patients with lower stages of fibrosis. (5, 6) Currently, there are no approved pharmacological interventions for NASH. (7) Lifestyle measures, including dietary changes and exercise have important benefits on NASH, however, significant body weight reduction (>7%) is required to improve NASH and fibrosis, (8) which is difficult to achieve and harder to sustain over time. (8) Thus, there is an urgent need to develop safe and effective therapeutic options for patients with NASH, particularly targeting those with advanced liver fibrosis. Several drugs with different mechanism of actions and targets have been evaluated and/or are currently being tested for NASH, including vitamin E (9-12), pioglitazone (13) obeticholic acid (14), elafibranor (15), cenicriviroc (16), liraglutide (17) and selonsertib (18). Although most of them have shown clear beneficial effects on liver histology, including NASH resolution and fibrosis regression (surrogate markers of clinical outcomes), no efficacy data exist on longterm survival and clinical outcomes. A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. Oxidative stress is suspected to play an important role in the progression to NASH and advanced fibrosis in NAFLD patients. Previous studies have confirmed a strong relationship between the severity of NAFLD and degree of oxidative stress. (19) Epidemiological studies have reported that low plasma levels of vitamin E are not only associated with presence of NASH(20) but also with increased all-cause mortality among NAFLD patients. (21) Vitamin E (α-tocopherol) is a well-known antioxidant that can protect cellular structure integrity against injury from lipid peroxidation and oxygen-free radicals. Several randomized controlled trials (RCT) have explored the efficacy of the supplementation of vitamin E 800 I/U/day on liver histology and aminotransferase levels of patients with NASH. (9-12) In two well-designed RCT conducted in adult and pediatric biopsy-proven NASH, vitamin E was associated with significant improvement in NASH histology, although there was no significant regression in liver fibrosis as compared with the placebo group. (9, 11) These results prompted the American Association for the Study of Liver Diseases (AASLD) to recommend vitamin E 800 I/U/day in nondiabetic and noncirrhotic patients with biopsy-confirmed NASH. (22) We conducted a study to investigate the impact of the vitamin E administration on long-term clinical outcomes in patients with biopsy-proven NASH and advanced fibrosis followed for up to 10 years in an academic tertiary referral center in the United States. MATERIALS AND METHODS