Faghihzadeh F, Adibi P, Hekmatdoost A. The effects of resveratrol supplementation on cardiovascular risk factors in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled study. Br J Nutr. August 3, 2015; [epub ahead of print]. doi: 10.1017/S0007114515002433.

The incidence of non-alcoholic fatty liver disease (NAFLD) is on the rise and its occurrence is strongly correlated with metabolic syndrome (obesity, hyperlipidemia, hypertension, insulin resistance, and type 2 diabetes). NAFLD is characterized by fatty deposits in the liver (steatosis) and is diagnosed based on medical history, elevated levels of liver enzymes such as alanine aminotransferase (ALT), and ultrasonography. Lifestyle changes in diet and exercise are commonly recommended as there are no drug therapies, although there is some evidence that glycemic drugs may provide some benefits. Studies also suggest that adjuvant supplementation with antioxidant and anti-inflammatory natural products may provide more benefits than lifestyle adjustments alone. Resveratrol, a polyphenolic compound found in grape (Vitis vinifera, Vitaceae) seeds, among other plant species, has anti-inflammatory and antioxidant properties and has demonstrated positive effects in animal models with NAFLD. Although resveratrol has been shown to mimic the metabolic effects of caloric restriction and improve glucose metabolism in humans, the results of clinical trials in patients with NAFLD have been conflicting. This double-blind, randomized, placebo-controlled trial investigated effects of resveratrol supplementation in patients with NAFLD. 

Patients (n=127) referred to the Isfahan Fatty Liver Clinic at the Isfahan University of Medical Sciences in Isfahan, Iran, were screened. Inclusion criteria were high serum ALT levels (>30 IU/l in men and >19 IU/l in women), steatosis confirmed by ultrasound, and fibrosis on the FibroScan^® (Echosens™; Paris, France) assay for 6 months or more prior to the study. The exclusion criteria were as follows: viral hepatitis, alcohol-related liver problems, diabetes, untreated hypothyroidism, other systemic or psychological diseases, pregnancy, lactation, absence of birth control, patients younger than 18 years old, and changes in the measured physiological parameters >10% compared to baseline. In total, 50 patients were randomly assigned to receive either a 500-mg capsule of trans-resveratrol (Sumabe; Port Macquarie, New South Wales, Australia) or placebo (edible paraffin) daily for 12 weeks. No other information about the resveratrol supplement is given. At baseline, all patients were advised on energy-balanced diet and exercise modifications (30 minutes of exercise 3 times per week).

At baseline, 4, 8, and 12 weeks, the following data were collected: medical history, physical measurements, 24 h dietary recall for 3 days (to assess energy intake), metabolic equivalent of task (MET) questionnaire was completed to assess physical activity, and adverse effects were queried. At baseline and 12 weeks, analysis of fasting blood samples and the FibroScan assay were conducted. Treatments were dispensed in 4-week allotments and unused capsules were returned at the next study visit to provide a measure of compliance. Primary outcome was significant reduction in ALT concentrations. The secondary outcomes were changes in FibroScan scores (a measurement of fibrosis), physical parameters, blood pressure, serum levels of glucose, lipids, insulin, other liver enzymes, bilirubin, and insulin sensitivity index.

Of the 50 patients who were randomly allocated, 1 patient in the resveratrol group dropped out of the study for "personal reasons" and 1 patient in the placebo group was dropped from analysis due to weight loss in excess of 10%. No adverse side effects were reported. Physical and biochemical characteristics were not different between groups at baseline; however, ALT concentrations were lower in the placebo group than in the resveratrol group, approaching significance (P=0.081). This was also seen for degree of fibrosis (P=0.05, less in the placebo group). Following the study, both body mass index (BMI) and waist circumference were significantly decreased in both groups (P<0.05). No differences were detected between the groups.

Although no differences were observed in energy intake between or within groups at the end of the study, the decrease in caloric intake from baseline to endpoint of the resveratrol group approached significance (2,265 ± 376.46 kcal/day vs. 2,049.3 ± 402.48 kcal/day, P=0.062). At the end of the study, the resveratrol group had a significantly greater decrease of ALT (−32.38% change vs. −13.54% change, P=0.03) and steatosis (P<0.05) as compared with placebo. Although aspartate aminotransferase (AST, a marker of liver damage) was significantly decreased in both groups (P=0.002 for both), the difference in percentage change was not significant between groups (P=0.065).

Bilirubin concentrations were also significantly decreased in both the resveratrol and placebo groups at the end of the study (P=0.026 and P=0.025, respectively). Also, total cholesterol was significantly elevated in the resveratrol group as compared with placebo (P<0.05), and low-density lipoprotein (LDL) cholesterol was also elevated in this group (P=0.07). High-density lipoprotein (HDL) cholesterol was significantly decreased in both groups (P<0.05 for both). Glucose concentrations were not significantly changed in either group; however, the change in insulin concentrations was significantly greater in the placebo group as compared with the resveratrol group (−22.05% change vs. −3.23% change, P<0.05). Also, homeostatic model assessments of insulin resistance and β-cell function (HOMA-IR and HOMA-β, respectively) were both significantly reduced in the placebo group at the end of the study, indicating improvement (P=0.03 and P=0.007, respectively). Systolic blood pressure decreased significantly in the resveratrol group as compared with the placebo group (−11.60% change vs. −2.78% change, P=0.001). Diastolic blood pressure was unaffected. 

This study shows that resveratrol intake in patients with NAFLD decreased ALT and steatosis, indicating potential efficacy for this population. Improved metabolic parameters in the placebo group may reflect those observed with weight loss and increased exercise, as this group had a greater change in BMI. Although this was not significantly different from the resveratrol group, it may be clinically relevant. Stated weaknesses include lack of liver biopsy and serum measurement of resveratrol. Also, this study may be somewhat confounded by discrepancies in baseline parameters, particularly in ALT. Further confirmation of resveratrol's efficacy and mechanism of action in NAFLD is necessary.