Table 2.
Clinical trials showing the effects of some polyphenols in liver conditions (MAFLD).
| Reference | Model/Country | Population | Intervention/Comparison | Outcomes | Side Effects |
|---|---|---|---|---|---|
| Anthocyanin | |||||
| [386] | Randomized, double-blind, placebo-controlled pilot trial | 33 patients (20 in the anthocyanin group, 13 in the control group | 320 mg/day or placebo for 12 and 24 weeks | There was a higher reduction in ALT in the anthocyanin group than in the placebo group (−19.1% vs. −3.1%, p = 0.02). | NR |
| [387] | Case–control and a randomized controlled intervention trial | 312 MAFLD patients | 320 mg/day or placebo for 12 weeks | The mRNA expression of NLRP3 inflammasome components (caspase-1, IL-1β, and IL-18) in PBMCs and also the plasma levels of IL-1β and IL-18 were dramatically decreased in treated NAFLD patients compared with controls. | NR |
| Catechin | |||||
| [388] | Randomized, double-blind study | 17 patients with MAFLD | Participants consumed green tea with high-density catechins, low-density catechins, or a placebo for 12 weeks. | All participants in the high-density catechin group had a significantly improved liver-to-spleen computed tomography (CT) attenuation ratio compared to the other groups; they also had reduced body fat, AST and ALT, and urinary 8-isoprostane excretion. In conclusion, the use of 700 mL/d green tea with >1 g catechin improved liver fat content and inflammation by decreasing oxidative stress. | NR |
| Chlorogenic acid and luteolin | |||||
| [389] | Randomized, double-blind, placebo-controlled. Italy, Spain, Poland, USA. |
100 individuals with MetS. (28♂, 22♀, 63 ± 11 y); 50 randomized (26♂, 24♀, 63 ± 8 y) | 50 subjects were randomized to Altilix® (supplement with chlorogenic acid and luteolin)/6 months | There was a significant amelioration in the treated group compared to placebo in most parameters evaluated, including body weight, waist circumference, glycated hemoglobin, lipid plasma levels, liver transaminases, flow-mediated dilation, and carotid intima–media thickness. Supplementation with Altilix® improved hepatic and cardiometabolic parameters in individuals with MS. | Transient gastrointestinal symptoms (n = 2 on Altilix® and 3 on placebo) |
| Curcumin | |||||
| [390] | Randomized, double-blind, placebo-controlled clinical trial | 50 patients with MAFLD, 18 y or more | 25 patients were assigned to receive placebo or 500 mg of curcumin or placebo/3 times a day/12 weeks | The intake of curcumin was associated with a significant decrease in liver fibrosis (p < 0.001) and NF-kB activity (p < 0.05). Hepatic steatosis and liver enzymes and TNF-α were significantly reduced in both groups (p < 0.05). | NR |
| [391] | Randomized, double-blind, placebo-controlled study | 65 patients allocated to curcumin or placebo | Curcumin and placebo recipient groups using a block randomized design for 8 weeks | There was a significant increase in HDL-c levels in the curcumin group (p = 0.01); serum adiponectin increased significantly (p < 0.001), and leptin reduced significantly (p < 0.001) (decrease in the leptin–adiponectin ratio in the curcumin group). |
No AE |
| [392] | Double-blind parallel design. Iran | 54 patients with MAFLD | Phytosomal curcumin (250 mg/day) or placebo/8 weeks | There was a significant reduction in methylation in the promoter regions of the MutL homolog 1 (MLH1) and the MutS homolog 2 (MSH2). A comparison between groups did not indicate significant changes in anthropometric variables, except for BMI. Liver enzymes and 8-OHdG did not change significantly at the end of this study, and neither in the curcumin group nor in the placebo group did they change. | NR |
| [393] | Prospective, randomized study | 45♀ obese women with fatty liver disease | Participants were assigned to resistance training (RT), curcumin supplement, resistance training with curcumin (RTC), and placebo | ALT and AST decreased significantly in the RT and RTC groups (p ≤ 0.05) but not in the curcumin and placebo groups (p > 0.05). Alkaline phosphatase, total bilirubin, platelet count, and liver structure did not change significantly in all groups. Resistance training alone and with curcumin supplementation could significantly improve liver function, while taking curcumin alone had no significant effect on it. | NR |
| [394] | Randomized, double-blind, parallel-group, placebo-controlled clinical trial | 80 individuals 18 y–70 y (BMI: 25–30 kg/m2) and glycemia 100–125 mg/dL |
Participants received 2 capsules /day of 800 mg phytosomal curcumin | After 56 days of treatment, the curcumin-treated group showed a significant amelioration in fasting plasma insulin, HOMA index, waist circumference, blood pressure, triglycerides, HDL-c, hepatic transaminases, gamma-GT, hepatic steatosis index, and serum cortisol compared to baseline. Triglycerides, liver transaminases, fatty liver index, and cortisol levels also improved significantly compared to the placebo. | NR |
| [395] | Double-blind, parallel-group trial | 37 obese, non-diabetic individuals | Participants received curcumin or placebo/6 weeks | In comparison to placebo, curcumin showed no significant effects on liver fat content in obese individuals with mild steatosis. | Dyspnea (n = 1) |
| [396] | Double-blind, randomized trial | 80 patients with non-alcoholic simple fatty liver disease | Participants received 500 mg/d curcumin or placebo/24 weeks | There was a significant reduction in the liver fat content, free fatty acid, triglycerides, fasting blood glucose glycated hemoglobin, and insulin | |
| Epigallocatechin-gallate | |||||
| [359] | Double-blind, placebo-controlled clinical trial | 30 obese subjects were allocated into EGCG-supplemented group or placebo | Participants received 300 mg per day of EGCG for 8 weeks | EGCG significantly reduced systolic and diastolic blood pressure (p < 0.05), fasting plasma triglyceride (p < 0.05), and serum kisspeptin levels (p < 0.05) after the treatment. | Headache (n = 1) |
| Puerarin | |||||
| [397] | Randomized, double-blind, placebo-controlled, 2-way crossover trial | 217 Chinese ♂, 18–50 y without a history of heart disease | Participants were randomized to receive puerarin (90.2 mg daily) or placebo, followed by a 4-week washout, and then crossed over to the other intervention | No significant modifications were seen in lipid profile, blood pressure, high-sensitive C-reactive protein, liver or renal function after the treatment with puerarin. There was a significant decrease in glycemia. | NR |
| Quercetin | |||||
| [398] | Double-blind, placebo-controlled crossover study | 93 overweight or obese subjects aged 25–65 y with MS | Participants received 150 mg quercetin a day/six-week treatment periods separated by a five-week washout phase | Participants treated with quercetin showed a significant reduction in systolic blood pressure, but lipid levels, C-reactive protein, and TNF-α were not altered. Quercetin significantly reduced the plasma concentrations of atherogenic oxidized LDL-c. | NR |
| Resveratrol | |||||
| [399] | Randomized, double-blind, controlled clinical trial | 50 MAFLD patients | Participants received 500 mg resveratrol capsule or a placebo/12 weeks | The group treated with resveratrol had a significantly reduced hepatic steatosis grade, ALT, AST, NFKB, inflammatory cytokines, and serum cytokeratin-18 compared with placebo. | NR |
| [400] | Double-blind, randomized, placebo-controlled trial | 60 participants with MAFLD | Participants received 2150 mg resveratrol capsules or placebo 2 times a day/3 months | The group treated with resveratrol had significantly reduced ALT, AST LDL-c, glycemia, HOMA, total cholesterol TNF-α, cytokeratin 18 fragment, and fibroblast growth factor 21. There was an increase in adiponectin levels. | NR |
| [401] | Single-center, randomized, double-blind, placebo-controlled study | 112 men and women with BMI > 27 kg/m2; 18–70 y | Participants received resveratrol 150 mg/day or placebo for 12 weeks | There was a change in liver fat content after treatment as well as in the visceral and subcutaneous abdominal fat mass and a reduction in glycemia, HOMA index, and other cardiovascular risk factors. | NR |
| [402] | Randomized controlled clinical trial | 90 patients with MAFLD (both genera); 20–60 y with BMI 25 to 35 kg/m2. | Participants were divided into 3 intervention groups: one that received a low-calorie diet, the resveratrol group received 600 mg pure trans-resveratrol (2 × 300 mg/day), and the placebo group/12 weeks | There was a significant reduction in weight and BMI observed in the resveratrol group compared to the placebo group. No modifications were seen in the lipid profile, ALT, AST, hepatic steatosis grade, serum glycemic parameters, and lipid profiles in the resveratrol group (all p > 0.05). | NR |
| [403] | Randomized, double-blind, placebo-controlled clinical trial | 50 patients with MAFLD; 20–60 years | Participants received 600 mg resveratrol/ day or placebo/12 weeks | The use of resveratrol significantly reduced waist circumference, body weight, and BMI when compared to the placebo. No significant modifications were observed in lipid profile (ApoA1, ApoB, and ox-LDL), atherogenic indices, AST, ALT, and γ-GT, and blood pressure. | NR |
| [404] | Double-blind, randomized controlled trial | 76 patients with T2DM | Participants received 1000 mg/day resveratrol or placebo/8 weeks | The supplementation with resveratrol did not produce effects on hepatic steatosis and cardiovascular indices. | NR |
| Silymarin | |||||
| [405] | Open preliminary pilot study | 85 participants with MAFLD | Patients received silybin + vitamin E + phospholipids—RealSIL | The use of silybin + vitamin E+ phospholipids can improve insulin resistance and the plasma levels of markers of liver fibrosis. | NR |
| [406] | Preliminary study | 59 were affected by primitive MAFLD | Patients received silybin + vitamin E + phospholipids—RealSIL, 4 pieces of silybin (94 mg each piece) /day/6 months followed by more 6 months of follow up | The treated patients showed improved liver enzyme levels, reduced hyperinsulinemia, and an improvement in all liver fibrosis indices. | NR |
| [407] | Multicenter, phase III, double-blind clinical trial | 179 patients with MAFLD | Patients received Realsil (silybin plus phosphatidylcholine) or placebo twice daily/12 months | The treatment with Realsil significantly reduced HOMA, liver enzyme levels, and BMI. There were improvements in fibrogenesis markers. | Diarrhea, dysgeusia, and pruritus |
| [408] | Randomized clinical pilot study | 36 patients with MAFLD | Patients received 2 tablets of silymarin plus vitamin E (Eurosil 85®, MEDAS SL)/day/3 months | Associated with lifestyle modifications, silymarin reduced anthropometric parameters, γ-GT levels, and MAFLD index. | NR |
| [409] | Open-controlled clinical trial | 78 patients with MS and liver steatosis | One group received Eurosil 85(®) (silymarin + vitamin E), and the other received placebo | The participants who received the silymarin supplement had reduced BMI, abdominal circumference, ultrasound measurement of the right liver lobe, and adipose visceral indices. | NR |
| [410] | Randomized, double-blind, placebo-controlled trial | 99 adults with NASH and MAFLD activity score of 4 | Participants received silymarin (700 mg) or placebo 3 times/day/48 weeks | The group treated with silymarin had a significantly reduced fibrosis-AST-to-platelet ratio index, fibrosis-4 score, and MAFLD fibrosis score. | NR |
| [411] | Double-blind randomized trial | Sedentary men and women with BMI ≤ 34.9 kg/m2 | Participants were divided into Novel Nutraceutical Supplement without silymarin or with silymarin extract (9%) (4 capsules/day) | There was a reduction in the waist circumference, as well as in the waist-to-height ratio and waist-to-hip ratio AST and ALT, and endocrine hormones cortisol and thyroid-stimulating hormone (TSH) at 90 and 180 days after supplementation with or without silymarin. | NR |
Abbreviations: AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI: body mass index; γ-GT: Gamma-Glutamyltransferase; HDL-c: high-density lipoprotein cholesterol; HOMA: Homeostatic Model Assessment; MAFLD: Metabolic-Associated Fatty Liver Disease; MS: metabolic syndrome; NF-kB: nuclear factor kappa B; PBMCs: peripheral blood mononuclear cells; T2DM: type 2 diabetes mellitus.