Table 2.
Summary data of patients in included studies.
| Author, setting and country | Study design | Population | Treatment | Study duration | Follow up | Conclusion | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| Intervention | Number | Dosage | Frequency | Co-Intervention | ||||||
| Mosca et al.23
(Italy) |
Randomized double-blinded, placebo-controlled
trial (Conference Paper) |
Adolescents (age range, 4−16 years) with liver biopsy proven NAFLD and without other causes of liver disease. | vitamin E | 40 | __ | __ | Hydroxytyrosol | NA | 4 months | - Vitamin E and Hydroxytyrosol reduced the
systemic inflammation with a significantly decrease of
IL-6. - The combination increased the expression of IL-10, which is able to inhibit the synthesis of pro-inflammatory cytokines. |
| Placebo | 40 | __ | __ | None | ||||||
| Khachidze et al.32
(Georgia) |
Randomized double-blinded, placebo-controlled
trial (Conference Paper) |
Patients with elevated aminotransferase levels and drinking less than 40 g alcohol per week with a diagnosis of NASH. | vitamin E | 52 | 400 IU | Once daily | vitamin C 500 mg/day + lifestyle modification | NA | 12 months | Vitamin E plus vitamin C combination is an effective, safe and inexpensive treatment option in patients with NASH and may be useful to reduce damage from oxidative stress and slow the process leading to cirrhosis. |
| lifestyle modification | 20 | __ | __ | None | ||||||
| UDCA | 35 | 15 mg/kg | Once daily | lifestyle modification | ||||||
| Anushiravani et al.31
(Iran) |
Randomized double-blinded, placebo-controlled trial | Patients aged between 18 and 65 years with a probable diagnosis of NAFLD in liver sonography (grades II and III steatosis) with or without increased levels of liver enzymes AST and ALT (above 20 mg/dl for women and 30 mg/dl for men). | vitamin E | 30 | 400 IU | Once daily | lifestyle | April 2016 − October 2017 | 3 months | - Vitamin E shows a significant benefit in improving liver aminotransferases in patients with NAFLD after only 3 months, without exerting any specific side effects. |
| Placebo | 30 | __ | __ | lifestyle | ||||||
| Metformin | 30 | 500 mg | Once daily | lifestyle | ||||||
| Silymarin | 30 | 140 mg | Once daily | lifestyle | ||||||
| pioglitazone | 30 | 15 mg | Once daily | lifestyle | ||||||
| Bril et al.30
(United States) |
Randomized, double-blind, placebo-controlled trial | Patients aged between 18 and 70 years with a diagnosis of type 2 diabetes mellitus, based on prior medical history, results from prior laboratories (hemoglobin A1C or fasting plasma glucose), and with a diagnosis of NASH based on a liver biopsy, and defined as: zone 3 accentuation of macrovesicular steatosis (any grade), hepatocellular ballooning (any degree) and lobular inflammatory infiltrates (any amount). | vitamin E | 36 | 400 IU | twice day | None | June 2010– September 2016 | 18 months | - Combination therapy was better than placebo in
improving liver histology in patients with NASH and
T2DM. - Vitamin E alone did not significantly change the primary histological outcome. |
| Placebo | 32 | __ | __ | None | ||||||
| vitamin E | 37 | 400 IU | twice day | pioglitazone 45 mg/day | ||||||
| Zöhrer et al.20
(Italy) |
Randomized, double-blind, placebo-controlled trial | Children or adolescents (age range, 4–16 years) with liver biopsy-proven NASH and without other causes of liver disease. | vitamin E | 20 | 39 IU | Once daily | choline 201 mg + DHA 250 mg | NA | 12 months | - Combination of DHA, vitamin E and choline could improve steatosis and reduce ALT and glucose levels in children with NASH. |
| Placebo | 20 | __ | __ | None | ||||||
| Aller et al.26
(Spain) |
Randomized clinical pilot study | Patients with diagnosis of NAFLD confirmed by percutaneous liver biopsy. | vitamin E | 18 | 80 IU | Once daily | silymarin + hypocaloric diet + exercise | NA | 3 months | - Vitamin E plus silymarin and a hypocaloric
diet ameliorate function hepatic test, and non-invasive
NAFLD index. - Silymarin can be an alternative valid therapeutic option particularly when other drugs are not indicated or have failed or as a complementary treatment associated with other therapeutic programs. |
| hypocaloric diet | 18 | __ | __ | None | ||||||
| Lavine et al.9
(United States) |
Randomized, double-blind, double-dummy, placebo controlled clinical trial | Patients aged 8−17 years with NAFLD by a liver biopsy demonstrating more than 5% steatosis within a 6-month period before randomization and persistently elevated levels of ALT was defined by a value greater than 60 U/L for 1−6 months before and at the time of randomization. | vitamin E | 58 | 800 IU | Once daily | diet + exercise | September 2005−March 2010. |
24 months | - Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD. |
| placebo | 58 | __ | __ | diet + exercise | ||||||
| metformin | 57 | 1000 mg | __ | diet + exercise | ||||||
| Sanyal et al.29
(United States) |
Phase III, multicenter, randomized, double-blind, placebo controlled, clinical trial |
adults without diabetes who had nonalcoholic steatohepatitis by a liver biopsy within 6 months before randomization. | vitamin E | 84 | 800 IU | Once daily | None | January 2005−January 2007 | 24 months | - Vitamin E was superior to placebo for the
treatment of NASH in adults without diabetes. - There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. |
| placebo | 83 | __ | Once daily | None | ||||||
| pioglitazone | 80 | 30 mg | Once daily | None | ||||||
| Balmer et al.27
(Switzerland) |
Randomized, placebo-controlled, double-blind study | Patients 18−75 years of age with histologically proven NASH by a liver biopsy. | vitamin E | 14 | 400 IU | twice day | UDCA 12–15 mg/kg/day | NA | 24 months | - UDCA + Vit E improves not only
aminotransferase levels and liver histology of patients with NASH, but also decreases hepatocellular apoptosis and restores circulating levels of adiponectin. - UDCA1VitE combination has metabolic effects in addition to its beneficial cytoprotective properties. |
| placebo | 13 | __ | __ | None | ||||||
| UDCA | 14 | 12−15 mg/kg | Once daily | None | ||||||
| Wang et al.33
(China) |
Randomized, Single-blind study | Obese children, according to the criteria that a child is obese when the BMI exceeded the 95th BMI percentage for age and sex. The patients age ranged from 10 to 17 years (mean 13.7 ± 1.9 years). They were all obese with liver fatty infiltration in ultrasonic appearance and abnormal liver function with higher ALT by at least 1.5 times over the upper normal limit which was diagnosed as NASH. | vitamin E | 19 | 150 IU | Once daily | None | NA | 1 month | - Short-term lifestyle intervention and vitamin
E therapy have an effect on NAFLD in obese
children. - Compared with vitamin E, lifestyle intervention is more effective. Therefore, lifestyle intervention should represent the first step in the management of children with NAFLD. |
| lifestyle intervention | 19 | __ | __ | None | ||||||
| no intervention | 38 | __ | __ | None | ||||||
| Nobili et al.21
(Italy) |
Randomized, placebo-controlled, double-blind study | children or adolescents with diagnosis of NAFLD by a liver biopsy and diffusely echogenic liver on imaging studies. Patients had persistently elevated serum aminotransferase levels. | vitamin E | 25 | 600 IU | Once daily | vitamin C 500 mg/day + diet + exercise | January 2003 − October 2006 | 24 months | - Lifestyle intervention with diet and increased
physical activity induces weight loss and is associated with
a significant improvement in liver histology and laboratory
abnormalities in pediatric NAFLD. - Vitamin E plus ascorbic acid does not seem to increase the efficacy of lifestyle intervention alone. |
| placebo | 28 | __ | __ | diet + exercise | ||||||
| Nobili et al.22
(Italy) |
Randomized, placebo-controlled, double-blind study | children or adolescents (aged 3−18 years) with biopsy-proven NAFLD and diffusely echogenic liver in imaging studies. Patients had persistently elevated serum aminotransferase levels. | vitamin E | 45 | 600 IU | Once daily | vitamin C 500 mg/day | January 2003 − March 2005 | 12 months | Diet and physical exercise in NAFLD children seem to lead to a significant improvement of liver function and glucose metabolism beyond any antioxidant therapy. |
| placebo | 43 | __ | __ | diet + exercise | ||||||
| Dufour et al.25
(Switzerland) |
Multicenter randomized, prospective, double-blind, placebo-controlled trial | Patients 18−75 years of age with a persistent elevation of serum ALT levels of at least 1.5 times the upper limit of normal for at least 6 months and a weekly alcohol consumption of less than 40 g were eligible. Patients had a liver biopsy showing macrovesicular steatosis of more than 10% of the hepatocytes, hepatocellular injury (ballooning, dropout), and lobular inflammation. | vitamin E | 15 | 400 IU | twice day | UDCA 12−15 mg/kg/day | January 1999 − December 2002 | 24 months | - Vitamin E in combination with UDCA improved
laboratory values and hepatic steatosis of patients with NASH. |
| placebo | 15 | __ | __ | None | ||||||
| UDCA | 18 | 12−15 mg/kg | Once daily | placebo | ||||||
| Vajro et al.24
(Italy) |
Randomized, placebo-controlled, Single-blind study | Patients with a probable diagnosis of NAFLD in liver sonography with increased levels of liver enzymes AST and ALT ⩾ 1.5 times above normal values for more than 6 months. | vitamin E | 14 | 600 IU × 2 months | Once daily | diet | January 1999 − June 2001 | 5 months | Oral vitamin E warrants consideration in obesity related liver dysfunction for children unable to adhere to low-calorie diets. |
| 150 IU × 3 months | Once daily | |||||||||
| placebo | 14 | __ | __ | diet | ||||||
| Harrison et al.28
(United States) |
Prospective, randomized, double-blind, placebo-controlled trial | Patients with a probable diagnosis of NASH 18 years of age or older and had a liver biopsy within the past 6 months for elevated aminotransferases. Hb values of at least 12 g/dl for women and 13 g/dl for men, white blood cell count of greater than 3000/mm3, neutrophil count of greater than 1500/mm3, platelets greater than 70,000/mm3, serum albumin greater than 3 g/dl, and a serum creatinine less than 1.4 mg/dl. | vitamin E | 23 | 1000 IU | Once daily | vitamin C 1000 mg/day + Diet + exercise | August 2000 – June 2002. | 6 months | - Vitamin E and vitamin C were well tolerated
and were effective in improving fibrosis scores in NASH
patients. - No improvement in necroinflammatory activity or ALT was seen with this combination of drug therapy. |
| placebo | 22 | __ | __ | Diet + exercise |
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DHA, docosahexaenoic acid; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH, nonalcoholic steatohepatitis; UDCA, ursodeoxycholic acid.