Table 2: Summary of design, methodology and results of omega-3 PUFAs supplementation in human trials of
NAFLD/NASH*
Rank
1.
Author, ref.
Capanni
89
Population
(n) - Primary
diagnosis
et al. n = 56
NAFLD on
ultrasound.
2.
Spadaro
31
et al.
n = 36
NAFLD on
ultrasound.
Study
format
Control
population (n)
-- Control arm
Treatment
population (n) –
Treatment arm
Open label,
controlled, no
placebo, no
randomized
trial.
n = 14
n = 42
Observation
only (regular
treatment)
1 g ethyl PUFAs daily
(orally), EPA:DHA ratio:
0.9:1.5
Open label,
controlled,
random
number
sampling, no
n = 18
n=18
Diet alone (AHA
regular diet, energy
intake: 50%
AHA diet + 1 g fish
oil × 2 daily (orally),
weight-loss advice
Study
duration
12 months
6 months
Main treatment
results
Primary outcome: Liver
appearance on ultrasound.
 hepatic perfusion
(doppler perfusion index),
 hepatic steatosis,
IHTG.
 serum liver enzymes
(ALT, AST, γ-GT).
hepatic fibrosis: N/A.
 serum arachidonic acid
 ω-6: ω-3 ratio.
↔ BMI. -- No adverse
event.
Primary outcome: Liver
appearance on ultrasound,
transaminases.
 hepatic steatosis,
IHTG.
 serum liver enzymes
1
n =23
3.
Tanaka et al.
90
Lliver biopsy proven NASH
patients.
placebo,
single-blinded
trial.
carbohydrates, 20%
protein, 30% fat),
weight-loss advice.
(EPA+DHA: >85% of
PUFAs, ratio: 0.9–1.5)
Open label,
no
randomized,
no placebo
trial.
n = N/A
n= 23
Control arm: N/A
2.7 g
highly
(>98%)
purified EPA-ethyl ester,
daily.
12 months
(ALT, γ-GT), serum TNFα.
↔ AST.
 HOM-IR.
 serum HDL.
hepatic fibrosis: N/A.
BMI decreased to similar
extents in both groups. -No adverse event.
Primary outcome: liver
appearance on ultrasound,
liver histology.  hepatic
steatosis (relative to
baseline).  liver enzymes
ALT, AST.  HOMA-IR.
↔ γ-GT.  lobular
inflammation, ballooning.
 NAS and fibrosis score
dropped ≥ 1 in 6/7 patients
(85%).  Serum free FAs,
total cholesterol, AA,
ferritin, thioredoxin. 
Plasma sTNF-R1, sTNFR2 levels -- No adverse
event.
2
4.
Vega et al.
95
n=16
NAFLD on
magnetic
resonance
spectroscopy
(MRS).
n=52
5.
Itoh et al.
60
Obesity.
n=144
6.
F.S. Zhu et al
96
NAFLD with
hyperlipidemia
Open label,
no
randomized,
no placebo,
cross-over
design.
n=N/A
n= 16
No control arm
9 g of fish oil daily.
Single blind,
randomized,
no placebo
trial.
n=26
n=26
Dietary advice only.
1.8 g EPA daily (highly
purified EPA- ethyl ester,
purity >98%).
Randomized,
placebocontrolled,
triple-blind
trial.
n = 72
n = 72
2 g placebo × 3 daily, 6 AHA diet + weight loss
months + weight loss
advice + 2 g seal
advice.
oil × three times a day, for
6 months (520 mg ω-3:
Primary outcome
1 month of measures: Plasma and
hepatic triglycerides.
placebo
 serum triglyceride level.
followed
by
2 Hepatic fibrosis: N/A.
months of ↔ liver fat content.
PUFA
treatment.
3 months
6 months
Primary outcome: Serum
adiponectin.
Hepatic fibrosis: N/A.
 plasma triglycerides.
 serum adiponectin.
 hepatic steatosis. 
ALT. ↔ AST, γ-GT.
NASH score: N/A.
Adverse events: No
difference btw groups. 
TG.  NAFLD symptom
score, AST, γ-GT, total
and LDL cholesterol. 
3
EPA 175 mg, DPA
235 mg, DHA 110 mg).
7.
8.
Mario Kratz et n = 26
al 98
Obesity.
Sofi F. et al
99
n = 11
NAFLD on
ultrasound
Randomized,
controlled, no
placebo,
dietary
intervention
trial.
Randomized,
placebocontrolled,
dietary
intervention
trial.
HDL cholesterol (to
similar extents in both
groups).
3.5 months
n = 13
n = 13
Control diet (rich in
monounsaturated fatty
acids typically mixed
American diet,
consisting of 0.5% of
energy intake from ω–
3 PUFAs).
Control diet for the first
two weeks, than diet rich
in ω–3 PUFAs (3.5% of
energy intake) from both
plant and marine sources.
 total plasma
adiponectin. ↔ HMW
plasma adiponectin and
HMW: total plasma
adiponectin ratio in both
diet groups. ↔ fasting
glucose, insulin
concentrations, HOMA-IR
index, diurnal adiponectin
amplitude.
12 months
n=5
n=6
Dietary
recommendations +
olive oil not enriched
with ω-3 PUFAs.
Dietary recommendations
+ daily oral administration
of 6.5 ml olive oil
enriched with 0.83 g
omega-3 PUFAs (0.47 g
EPA + 0.24 g DHA).
 plasma liver enzymes
(AST, ALT and GGT). 
serum triglycerides. 
serum adiponectin levels.
 HDL.
Improvement of liver
ultrasonography.
4
2 months
9.
10.
Cussons A.J. et n = 25
101
al
Obese premenopaused
women with
PCOS
Doubleblinded,
placebocontrolled
trial with a
randomized
cross-over
design.
Control (placebo) diet:
4 × 1000 mg capsules
of olive oil containing
67% oleic acid, daily.
Hatzitolios et al
102
Uncontrolled
design, no
randomized,
no placebo
trial.
Alternative lipidn = 73
lowering
pharmacological agents 13.7 g omega-3, daily.
(orlistat, atorvastatin)
n = 73
Mixed
dyslipidemia,
persistent
transaminasemia,
hepatic fat
infiltration on
ultrasonography
and liver biopsy.
n = 25
Primary outcome measure:
hepatic fat content
(quantified by proton
MRS).
4g daily marine-derived
omega-3 PUFAs (56%
DHA + 27% EPA)
 liver fat content, 
serum triglycerides, 
blood pressure.
6 months
 serum transaminases.
Normalization of
ultrasonographic evidence
of fatty liver.
5
6 months
11.
Nobili V. et al. n = 60 children
103
or adolescents
(4-16 years)
Biopsy-proven
NAFLD.
Randomized,
placebocontrolled,
double-blind
interventional
study.
n = 20
n = 40
Placebo (290 mg
linoleic acid supplied
with germ oil).
DHA supplementation:
Main outcome measures:
 liver fat content. (by
ultrasonography).
Similarly in both DHA
groups:  insulin
sensitivity index  serum
triglycerides.
n = 20 (250 mg/day) and
n = 20 (500 mg/day)
(39% DHA oil obtained
from Schyzochitrium
↔ ALT and body mass
index.
12.
H.M. Parker et n=355
88
al
NAFLD/NASH
patients.
Meta-analysis
of data from 9
eligible trials
** (4 RCTs, 1
randomised
placebo
controlled
cross-over
design, 1
quasi
experimental
cross-over
Control group: 1 quasi
experimental design
trial (all participants
underwent omega-3
treatment + those who
refused treatment)
n = 355
Median ω-3 PUFA dose =
4 g/day (range: 0.83–
13.7 g/day).
Median
duration of
treatment
with
omega-3
PUFAs:
6 months
(range: 212 months).
Primary outcome
measures: liver fat and
function tests (ALT, AST).
 liver steatosis
(quantified by ultrasound,
magnetic resonance
spectroscopy or needle
biopsy). Benefits are seen
with more than 0.83 g/day
of omega-3
supplementation
No significant effect on
6
design, 2
uncontrolled
design, all
participants
underwent
omega-3
treatment.
liver tests. A no significant
trend favouring PUFA
treatment on ALT.
No reports of adverse
effects.
* Clinical trials conducted between 2004 – 2012.
Abbreviations: AA: arachidonic acid; AHA: American Heart Association; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI: body mass
index; FAs: fatty acids; γ-GT: gamma-glutamyl-transferase; GGT: g-glutamyl-transpeptidase; HDL: high-density lipoprotein; HMW: high-molecular weight;
HOMA-IR: homeostatic model assessment of insulin resistance; IHTG: intra-hepatic triglyceride; MRS: magnetic resonance spectroscopy; NAS: NAFLD
Activity Score; PCOS: polycystic ovary syndrome; sTNF-R: soluble tumor necrosis factor- receptor; TNF-α: tumor necrosis factor-alpha;
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