Omega-3 fatty acids for the treatment of non-alcoholic fatty liver disease

Table 1 Summary of trials design and results

Ref.	Study design	Intervention	Population	Outcome measurements	Results	Comments
Capanni et al[70]	Open-label	Oral administration of n-3 PUFA, 1-g capsule/d for 12 mo	56 patients with NAFLD (42 subjects receiving therapy; 14 controls)	AST, ALT, GGT, TG, FG, n-6/n-3, liver echo texture by US and liver perfusion by DPI	↓AST (P = 0.003) and ALT (P = 0.002), ↓ GGT (P = 0.03), ↓ TG (P = 0.02) and FG (P = 0.02) in comparison with controls. Circulating arachidonate and n6:n3 ratio was reduced (P = 0.0002, and P = 0.0001 respectively) in treated patients. Improvement of liver echo texture (P = 0.0001), and increase of DPI (P = 0.001)	Limits of this study are the absence of blinding and randomization, and the use for comparison of a self-selected small group consisting of those patients who had been declined entry to the treatment arm
Spadaro et al[72]	Randomized; open-label	AHA diet + 2 g/d n-3 PUFA (group DP) vs AHA diet (group D) for 6 mo	40 patients with NAFLD (group DP, n = 20; group D, n = 20)	Liver fat assessed by abdominal US, ALT, AST, TNF-α serum levels, and HOMA	In DP group: ↓ ALT (P < 0.01), TG (P < 0.01), serum TNF-α (P < 0.05) and HOMA (IR) (P < 0.05). Complete fatty liver regression in 33.4% of patients, and an overall reduction in 50%; In the D group: no significant modification of laboratory tests; no patient achieved complete regression of fatty liver, whereas some amount of reduction occurred in 27.7% of patients	Limits of the study are lack of placebo, and the non blinding of participants and investigators
Zhu et al[74]	Randomized	AHA diet + 2 g/d n-3 PUFA from seal oil (Group A) vs AHA diet + 2g of placebo (group B) for 6 mo	144 patients with NAFLD and hyperlipidemia (group A = 72; group B = 72)	Liver fat assessed by symptom scores, ALT and serum lipid levels after 8, 12, 16, and 24 wk; fatty liver assessed by US at weeks 12 and 24 after treatment	Group A vs group B showed ↓ of total symptoms score, ALT, TG, LDL (P < 0.05); complete fatty liver regression in 19.7% vs 7.35% (P = 0.004); In both groups there was a tendency in improvement in AST, GGT, TCHO and HDL levels (P < 0.05)
Tanaka et al[77]	Open label	EPA 2.7 g/d for 12 mo	23 patients with biopsy proven NAFLD	ALT, FFA, plasma soluble TNF receptor 1 and 2 levels, and serum ferritin and thioredoxin levels, body weight, blood glucose, insulin, and adiponectin concentrations; fatty liver infiltration assessed by histology	↓ ALT, AST, TG, TCHO, HOMA-IR, plasma thioredoxin; change in histological grade: steatosis: 2.4 (SD 0.5) vs 1.7 (SD 0.5); fibrosis: 1.7 (SD 1.1) vs 0.7 (SD 0.5); lobular inflammation: 2.1 (SD 0.7) vs 1.1 (SD 0.7); ballooning: 1.6 (SD 0.5) vs 0.9 (SD 0.4); NAS: 6.1 (SD 1.3) vs 3.7 (SD 1.4); Hepatic steatosis grade on the US changed from 2.1 ± 0.9 at baseline to 1.6 ± 1.1 after treatment (P = 0.004)	Limits of the study are the absence of a control group and small sample size
Sofi et al[75]	Randomized	Dietary recommendation + 6.5 mL/d of olive oil enriched with n-3 PUFA (0.83 g n-3 PUFA, of which 0.47 g EPA and 0.24 g DHA) for 12 mo vs dietary recommendation alone	11 patients with NAFLD assessed by US (intervention group, n = 6; control group, n = 5)	Liver fat content assessed by B-mode US and DPI; liver enzymes, TG and adiponectin levels	Intervention group vs controls showed a ↓ of AST (P = 0.02), ALT (P = 0.03), GGT (P = 0.03), TG (P = 0.04) levels; ↑ of HDL (P = 0.03), adiponectin (P = 0.04). There was a significant (P = 0.02) improvement of DPI in the intervention group, while no change was observed in the control group. Improvement of liver steatosis on US in the intervention group (% of patients at T0 and T12): absent (from 0% to 16.7%); mild (from 16.7% to 50%); moderate (from 33% to 0%); severe (from 50% to 33%)
Nobili et al[78]	Randomized	DHA (250 and 500 mg/d) vs placebo for 6 mo	60 children with biopsy-proven NAFLD randomly assigned to receive DHA 250 mg/d (n = 20), DHA 500 mg/d (n = 20) or placebo (n = 20)	Primary: change in liver fat content as detected by US; secondary: changes in ISI, ALT, TG and BMI	DHA 250 mg vs placebo: odds of more severe vs less severe steatosis (OR = 0.01, robust 95% CI: 0.002 to 0.11, P < 0.001); ↑ of ISI (P < 0.01), ↓TG (P < 0.05); ALT and SDS of BMI; DHA 500 mg vs placebo: (OR = 0.04, 0.002 to 0.46; P = 0.01); ↑ of ISI (P < 0.01), ↓TG (P < 0.05); ALT and SDS of BMI; DHA 250 mg vs DHA 200 mg: NS
Vega et al[79]	Open label	9 g/d of fish oil for 8 wk	22 patients with previous elevated liver fat on MRS (17 patients completed the trial)	Liver fat content assessed by B-mode US and DPI; liver enzymes, TG and adiponectin levels	↓ of plasma triglyceride level by 46% (P < 0.03), VLDL + IDL by 21% (P < 0.03), ApoB by 15% (P < 0.03). Liver fat content 7.9% pre-treatment; 8.0% after PUFA (NS)	Causes of liver disease other than NAFLD were not excluded and alcohol intake was not reported. It is unclear whether study participants received any other interventions such as diet or lifestyle advice

NAFLD: Non-alcoholic fatty liver disease; AST: Aspartate transaminase; ALT: Alanine transaminase; GGT: γ-glutamyl transpeptidase; TG: Triglycerides; FG: Fasting glucose; US: Ultrasonographic; DPI: Doppler perfusion index; AHA: American Heart Association; PUFA: Polyunsaturated fatty acid; TNF: Tumor necrosis factor; HOMA: Homeostatic model assessment; IR: Insulin resistance index; TCHO: Total cholesterol; HDL: High-density lipoprotein; MRS: Magnetic resonance spectroscopy; VLDL: Very low density lipoprotein; ISI: Insulin sensitivity index; EPA: Eicosapentaenoic acid; DHA: Docosahexaenoic acid; DPI: Doppler perfusion index; BMI: Body mass index; SDS: Standard deviation score; NS: Not significant.