Table 3.
Effects of n-3 PUFA supplementation in NAFLD (non-alcoholic fatty liver disease) and NASH (non-alcoholic steatohepatitis) adults.
| Reference | Study Design | Population | Intervention | Outcome Measurements | Results | Comments |
|---|---|---|---|---|---|---|
| Capanni et al., 2006. [200] | Open-label trial | Patients with NAFLD proven by US; Age range: 31–77 y. Mean BMI: 28.5 kg/m². n = 56 | Oral intake of n-3 PUFA (EPA and DHA in a 0.9/1.5 ratio), 1 g capsule a day for 12 months. Intervention group (n = 42) vs control group (n = 14) | Hematochemical tests; Liver fat changes detected by US and liver eco-texture measured by Duplex Doppler US and DPI follow up |
↓ AST, ALT, GGT; ↓ fasting TG and glucose ↓arachidonate ↓n-6/n-3 ratio Significant beneficial effects on liver US pattern and ↑ DPI |
Long-term n-3 PUFAS supplementation ameliorates hepatic steatosis in NAFLD patients |
| Spadaro et al., 2008. [111] | Randomized open-label trial | Patients with NAFLD proven by US; Mean age: 51 y Mean BMI: 30.5 kg/m² | AHA diet + 2 g/d n-3 PUFA (group DP, n = 20) AHA diet (Group D, n = 20) for 6 months |
Changes on liver fat via US; ALT, AST, GGT, lipid profile, TNF-α serum levels, fasting glucose, and IR by HOMA-IR | Group DP: ↓ ALT, GGT ↓ TG, TNF-α ↓ HOMA-IR ↑ HDL cholesterol Complete steatosis regression in 33.4 % of patients and an overall reduction of 50%. |
n-3 PUFA have a major improvement on fatty liver in patients with NAFLD |
| Zhu et al., 2008. [201] | Randomized controlled trial | Patients with US proven NAFLD associated with hyperlipidemia; Age: 18–65 y | Oral supplementation of n-3 PUFA for 24 weeks. AHA-based diet with a caloric restriction of 25-30 kcal/kg per day Group A (n = 66): 2 g n-3 PUFA from seal oils, 3 times/day. Group B (n = 68) 2 g placebo, three times/day |
Primary endpoints: fatty liver assessed by symptom scores, ALT and serum lipid levels at 8, 12, 16, and 24 weeks. Secondary endpoints: liver fat changes by US at weeks 12 and 24 |
After 24 wk of treatment: ↔ body weight, ↔ FBG; ↓ Total symptom scores, ↓ALT and TG Complete fatty liver regression was observed in 19.7% of the patients, and an overall reduction was found in 53.0% (35/66) of the patients in group A |
n-3 PUFA from seal oils is safe and efficacious for patients with NAFLD associated with hyperlipidemia and can improve their total symptom scores, ALT, serum lipid levels, and normalization of ultrasonographic evidence |
| Tanaka et al., 2008. [202] | Pilot Trial | 23 biopsy-proven NASH patients |
Highly purified EPA (2700 mg/d) was administered for 12 months | Biochemical parameters of glucose and lipid metabolism, inflammatory and iron metabolism oxidative-stress markers Ultrasonography Histologic evaluation of liver biopsies |
↓ ALT, AST ↓Total cholesterol ↓ sTNFR1,2 ↓Ferritin ↓ Thioredoxin ↓ hepatic steatosis and fibrosis, hepatocyte ballooning, and lobular inflammation |
EPA treatment seems to be safe and efficacious for patients with NASH |
| Sofi et al., 2010. [203] | Randomized | Patients with NAFLD proven by US. Age: 30–70 y, mean BMI: 29.3 kg/m² | Food consumption enriched with n-3 PUFA (0.47 g EPA + 0.24 g DHA) for 12 months. Group 1: (n = 6) 6.5ml/d enriched with olive oil + recommended diet Group 2: (n = 5) control (recommended diet + not enriched olive oil) |
Liver eco-texture measured by Duplex Doppler US and DPI. Liver enzymes, TG and adiponectin levels |
↓ ALT, AST, and GGT ↓TG level ↑HDL cholesterol ↑adiponectin ↑ DPI level |
Persistent consumption of food enriched with n-3 PUFA has favorable effects in patients with NAFLD |
| Scorletti et al., 2014. [204] | WELCOME study: double-blind, randomized, placebo-controlled trial | Patients with histological confirmation of NAFLD. Mean age: 50 years old. Mean BMI: 32.5 kg/m² | Intervention group (n = 51): oral supplementation of purified long-chain n-3 PUFA ethyl esters (1 g contains 460 mg of EPA and 380 mg of DHA), 4 g/day. Placebo group (n = 52): 4 g/day of olive oil. 15 to 18 months of treatment |
Liver fat percentage assessed by MRS and biomarker scores for liver fibrosis, erythrocyte enrichment quantification with DHA+EPA via gas chromatography | Trend to improve liver fat% with DHA+EPA No improvement in liver fibrosis scores |
Association between erythrocyte DHA enrichment with DHA+EPA treatment and a decrease of liver fat percentage |
| Sanyal et al., 2014. [205] | Double-blind, randomized, placebo-controlled trial | Patients with NASH, NAFLD activity scores ≥ 4, with minimum scores of 1 for steatosis and inflammation, along with either ballooning or at least stage 1a fibrosis. n = 243 | Subjects were randomly assigned to groups given placebo (n = 75), low- dosage EPA-E (1800 mg/d; n = 82), or high-dosage EPA-E (2700 mg/d; n = 86) for 12 months | The primary end point: NAFLD activity score ≤3, without worsening of fibrosis; or a decrease in NAFLD activity score by ≥2 with contribution from >1 parameter, without worsening of fibrosis. Liver enzymes, IR, adiponectin, keratin 18, hs-CRP, or hyaluronic acid were measured as well |
No effects of EPA-E on steatosis, inflammation, ballooning, or fibrosis scores. No effects on levels of liver enzymes, IR, adiponectin, keratin 18, hs-CRP, or hyaluronic acid. High-dosage EPA-E: ↓ levels of TG | In a phase 2 trial, EPA-E had no significant effect on the histologic features of NASH. EPA-E reduced subjects’ levels of triglyceride compared with placebo, without any increase in serious adverse events |
| Li et al., 2015. [206] | Randomized placebo-controlled trial | Patients diagnosed with NASH Mean age: 51 years old. Mean BMI: 27.9 kg/m² | Intervention group (n = 39): 50 mL of PUFA with 1:1 Ratio of EPA and DHA added into daily diet placebo: saline (n = 39). Duration of treatment: 6 months | Liver enzymes, lipid profile, markers of inflammation and oxidation, and histological changes by biopsy | Liver function was significantly improved: ↓ ALT / AST ↓ TG ↓Total Cholesterol ↓ CRP (inflammation) ↓ MDA (oxidation) ↓ fibrotic parameters |
6 months of n-3 PUFA therapy is beneficial for improving NASH |
| Argo et al., 2015. [207] | Double-blind, randomized, placebo-controlled trial | Patients 34 subjects with biopsy-proven NASH; Mean age: 47 y Mean BMI: 32.5 kg/m2 |
Oral supplementation of n-3 PUFA 3000 mg/d (each 1000 mg capsule contains 35% EPA, 25% DHA and 10% other n-3 PUFA), vs placebo (soybean oil). n = 17 per group 1 year of treatment |
Liver biopsy, Abdominal MRI for quantitative assessment of hepatic fat, AST, ALT, total cholesterol, LDL and HDL cholesterol, and TGs. FFAs, insulin, and glucose levels | No differences for the primary end point of NASH activity score (NAS) reduction. In n-3 PUFA-treated subjects: ↓in liver fat content by MRI (among subjects with increased or stable weight) |
Treatment did not exert beneficial effects towards hepatic histological improvement in NASH patients |
| Qin et al., 2015. [208] | A double-blind randomized Placebo-controlled clinical trial |
Patients with NAFLD associated with hyperlipidemia, Mean age: 44.3 ± 10.9 and 46.0 ± 10.6 y for placebo or treated group Mean BMI: 26.0 ± 2.8 and 26.4±3.9 kg/m², respectively. n = 70 |
Randomly assigned to consume fish oil (n = 36, 4 g/d) or corn oil capsules (n = 34, 4 g/d) for 3 months | Blood levels of lipids, glucose and insulin, liver enzymes, and cytokines at baseline and the end of the study were measured | Fish oil group: ↓ total cholesterol, ↓ TG, ↓apolipoprotein B ↓ glucose, ↓ ALT ↓ GGT ↑ Adiponectin ↓ TNF-α ↓ LTB4, ↓ FGF21, ↓ CK-18/M30 ↓PGE2 |
These findings suggest that fish oil can benefit metabolic abnormalities associated with NAFLD |
| Dasarathy et al., 2015. [209] | Double-blind, randomized, placebo-controlled trial | Patients with NAFLD and NASH diagnosed by liver biopsy, Mean age: 50 y. Mean BMI: 35 kg/m². n = 37 | n-3 PUFA group: oral supplementation of 2160 mg of EPA and 1440 mg of DHA. (n = 19) and Placebo group (n = 18) using corn oil supplementation Duration: 48 months |
Primary endpoints: assess the improvement of 2 points in the NAFLD activity score by liver biopsy. Secondary endpoints: changes in liver enzymes, IR, fasting glucose, and HbA1C |
No differences between groups in BMI, serum transaminases, diabetes control, histological evaluation of NAFLD activity score and individual components | N-3 PUFA supplementation showed no beneficial effects in NASH patients with diabetes |
| Nogueira et al., 2016 [210] | Double-blind, randomized, placebo-controlled trial | Men and women with a proven histological diagnosis of NASH. Mean age: 53.9 ± 1.8 and 52.5 ± 7.2 y for placebo group and n-3 PUFA group. Mean BMI: 30.3 ± 4.4 and 31.1 ± 4.6, respectively. n = 50 |
n-3 PUFA group: 3 capsules (0.945 g in total per day, 64% ALA, 16% EPA, and 21% DHA). (n = 27) Placebo group: 3 capsules of mineral oil (n = 23). Duration: 6 months |
Primary endpoints: Plasma fatty acids (ALA, EPA, DHA and AA), NAS. Secondary endpoints: serum TG, AST, ALT, GGT, fasting lipid profile, fasting glucose, anthropometric parameters, or plasma levels of IL-6 at baseline and at endpoint, |
n-3 PUFA group: ↑plasma ALA and EPA. NAS correlated with↑plasma ALA. ↓TG Control group: ↑plasma DHA and EPA, NAS correlated with↑plasma DHA and EPA |
No significant changes were observed on liver histology in the n-3 PUFA or placebo group |
| Tobin et al., 2018 [211] | Double-blind, randomized, placebo-controlled trial | Patients with previously diagnosed NAFLD (hepatic steatosis stage). Mean age; 55.1 ± 10.9 and 55.3 ± 13.3 y for placebo and n-3 PUFA MF4637 group Mean BMI; 32.4 ± 5.0 and 32.1±4.8. respectively. n = 176 |
n-3 PUFA group: oral supplementation of 3g capsule (1380 g of EPA and 1140 g of DHA) (n = 87) Placebo group: oral supplementation of 3 g olive oil capsule (n = 89) Duration = 24 weeks |
n-3 PUFA index, n-6 PUFA: n-3 PUFA ratio, quantitative measurements of RBC EPA and DHA at the baseline and the endpoint, liver fat content measured by MRI | n-3 PUFA group: ↑n-3 PUFA index and ↑absolute values of RBC EPA and DHA, ↓RBC n-6: n-3 ratio ↓liver fat content in both groups |
No significant differences in fat liver were found between n-3 PUFA and placebo group |
Abbreviations: NAFLD, non-alcoholic fatty liver disease; AST, aspartate transaminase; ALT, alanine transaminase; GGT, gamma-glutamyl transpeptidase; ↑, increased; ↓, decreased; ↔, not changed; TG, triglycerides; Chol: cholesterol; US, ultrasonography; DPI, doppler perfusion index; TNF-α, tumor necrosis factor-alpha; HOMA-IR, homeostasis model assessment-estimated IR; HDL, high density lipoprotein; FBG, fasting blood glucose; NS, not significant; CRP, C-reactive protein; MDA, malondialdehyde; EPA-E, ethyl-eicosapentanoic acid; MRI, magnetic resonance imaging; NAS, NASH activity score; ApoB, apolipoprotein B, FGF21, fibroblast growth factor 21; PGE2, prostaglandin E2; HbA1C, Hemoglobin A1c; RBC, red blood cells; MRI, magnetic resonance imaging.