Fatty acid composition but not quantity is an important indicator of Non-alcoholic Fatty Liver Disease: A Systematic Review

doi:10.21203/rs.3.rs-2651995/v1

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Fatty acid composition but not quantity is an important indicator of Non-alcoholic Fatty Liver Disease: A Systematic Review

https://doi.org/10.21203/rs.3.rs-2651995/v1

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published 04 Sep, 2023

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Background

There is still paucity on the effects of dietary and supplemental fatty acid on non-alcoholic fatty liver disease (NAFLD). The aim of this review is to systematically review and summarise the effect of fatty acids intake on liver related outcomes in adult patients with NAFLD.

Methods

The review was conducted using Cochrane CENTRAL Library, scopus, Embase, MEDLINE, PubMed, and Web of Science. A total of 2786 records were identified, and of these, 36 studies (31 were randomised control trials (RCTs), and 5 were case-control studies) were included. Quality assessment was conducted using the Revised Cochrane Risk of Bias tool and Joanna Briggs Institute checklists.

Results

Of 36 articles, 79% of RCTs and 66% of case-control studies had a low risk of bias. Potential heterogeneity has been observed in assessment of liver related outcomes. According to the RCTs, there was moderate evidence (3/6 studies) that a diet characterised by a high MUFA, PUFA and low SFA showed reduced liver fat and stiffness. The using of culinary fats that are high in MUFA (4/6 studies) reduces liver steatosis. n-3 PUFA supplementation in combination with a hypocaloric or heart healthy diet with a low SFA improved liver enzyme level (5/14 studies) and steatosis score (3/14 studies).

Conclusions

Effects on NAFLD parameters, including liver fat, stiffness and steatosis, were primarily related to fatty acid composition independent of energy intake. Further investigation is needed to determine the mechanism of specific fatty acid on the accumulation of liver fat.

Health sciences/Diseases/Gastrointestinal diseases/Liver diseases

Health sciences/Health care/Nutrition

Fatty acid

Diet

culinary fat

non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, and it currently affects approximately 25% of the adult population (1). In the Western world, including the United States, Europe and Brazil, NAFLD appears to be the most common cause of chronic liver disease in the adult population (2–4). Since the global estimated prevalence of NAFLD is expected to increase alarmingly (ranging from 6–35%)(5), action is urgently needed to reduce its global health and economic burden. While multiple interventions have been evaluated in clinical studies for the management of NAFLD, there is no consensus on the assessment of these patients or optimal pharmacological therapy (6). Hence, current treatment options are limited to lifestyle changes, including diet and exercise, which are cost-effective and efficacious for improving the prognosis of patients with NAFLD (6).

The liver is exposed to different types of fats (namely fatty acids, cholesterol and triacylglycerol) derived from the diet, as well as visceral adipose tissues through the hepatic portal vein, which may contribute to fatty liver disease and hepatic insulin resistance (7). Dietary fatty acids are associated with hepatic lipogenesis and may play a dual role in the pathogenesis of fatty liver disease as they are implicated in their development and conversely, the prevention or reversal of liver fat accumulation (8). Further, the dietary fatty acid composition is an important factor in NAFLD development since 15% of liver triacylglycerol originates from the diet (8). Thus, it is important to know the specific type of fatty acids in the diet that causes fat accumulation in liver cells and, consequently, NAFLD development. Saturated fatty acid-rich diets increase liver fat due to increased lipolysis, mediated by inflammatory pathways in adipose tissue (9). Several studies revealed that increased intake of saturated fats, trans fat and cholesterol are associated with a deterioration of clinical features of NAFLD (9, 10).

Conversely, unsaturated fat intake is associated with decreased lipolysis and preventing fat accumulation in the liver (11). Adequate consumption of polyunsaturated fatty acid (PUFA) has been associated with the improvement of NAFLD (12, 13). Previous systematic reviews and meta-analyses have shown that supplementation with n-3 PUFA significantly improved liver fat content, steatosis score (assessed by ultrasonography), and liver enzyme levels in patients with NAFLD (11–14). However, the effect of fatty acid intake on liver histological outcomes (i.e., steatosis, lobular inflammation, hepatocellular ballooning, fibrosis) are still inconclusive(13). Additionally, above mentioned systematic reviews, in general, have focused on fatty acids modification, particularly, n-3 PUFA supplementation. However, in a recent systematic review and meta-analysis that evaluated the effect of dietary interventions with different, quantitative, macronutrient compositions on hepatic steatosis attenuation, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipid profile, glucose metabolism markers, and anthropometric parameters among adults and the elderly (60 years and over) with NAFLD (1). In relation to the effect of dietary fatty acid pattern on NAFLD, the results showed that hypocaloric diet that contains lower proportion of fat or higher monounsaturated fat rich hypocaloric diet significantly reduce the degree of hepatic steatosis (assessed by ultrasonography) (1). However, the meta-analysis of 6 included studies showed no significant changes in degree of hepatic steatosis (1). Given that cooking oil is considered an important source of fatty acids, it is essential to evaluate the effects of various cooking oil fatty acids on NAFLD (15–19). Thus, considering the diversity of dietary fatty acids for NAFLD in this current review, we attempt to include all studies assessing the effects of dietary and supplemental fatty acids on liver related outcomes (i.e., histological outcomes, liver fats and liver enzyme levels) in adults with NAFLD.

The current systematic review was registered at the PROSPERO International Prospective Register of Systematic Reviews (Registration number: CRD42021243799). Additionally, the study was reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (Table S1).

Search strategy

A comprehensive literature search was conducted using electronic databases Cochrane CENTRAL Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Embase, MEDLINE, PubMed, and Web of Science. Three groups of key terms indicating the population, exposure and outcome of interest were adapted from an original search strategy to each of the databases. The search strategy (Table S2) was created in consultation with a librarian experienced in systematic literature reviews. Search terms, as a combination of MeSH terms and text words, were as follows: “non-alcoholic fatty liver disease”, “fatty liver, non-alcoholic”, “fatty livers, non-alcoholic”, “liver, non-alcoholic fatty”, “livers, non-alcoholic fatty”, “non-alcoholic fatty liver”, “non-alcoholic fatty livers”, “non-alcoholic steatohepatitis”, “steatohepatitis, non-alcoholic” for population and search terms; and “diet”, “fat”, “total fat”, “dietary fat”, “dietary fatty acid”, “fatty acids”, “fat-restricted”, “low fat diet”, “diet low fat”, “fat free”, “high fat diet”, “diet high-fat”, “polyunsaturated fatty acid”, “polyunsaturated fatty acids”, “PUFA”, “omega 3”, “n3”, “n-3”, “omega 3”, “omega-3”, “eicosapentaenoic acid”, “EPA”, “docosahexaenoic acid”, “DHA”, “monounsaturated fatty acids”, “MUFA”, “saturated fatty acid”, “saturated fatty acids”, “SFA”, “adults’, “18 years and over” combined through Boolean operators “OR” and “AND”.

Screening and selection criteria

At the first screening stage, the titles and abstracts were assessed based on inclusion and exclusion criteria for each record. Selection criteria are described in detail in Table 1. Next, all titles and abstracts of electronically identified studies were screened by two reviewers (AD and YT) independently. Finally, these two reviewers performed the second screening step for each selected article based on the eligibility criteria. Selected journals included all studies published until November 2021.

Table 1

PICOS criteria for inclusion and exclusion of studies
Parameter	Inclusion criteria	Exclusion criteria
Population	• Individuals aged ≥ 18 years with NAFLD confirmed.	• Individuals aged ≥ 18 years without a diagnosis of NAFLD • Individuals aged ≤ 18 years and with alcohol-induced hepatic steatosis, with advanced chronic liver disease such as cirrhosis, and using enteral or parenteral nutrition. • Mixed-population studies that included, in addition to patients with NAFLD, healthy individuals or those with diseases not separated by groups.
Intervention or exposure	• Dietary or supplementation fat and/or fatty acid consumption	• Studies do not indicate dietary or supplemental fatty acid intake. • Circulating concentration of fatty acids • Studies including other interventions in addition to fat or fatty acids consumption
Comparison	• The inactive control diet (such as a placebo, no treatment, usual care without dietary advice or a waiting list control) • Comparator diet • Non-exposure to the dietary fatty acid assessed	• Non-comparative studies
Outcomes	• Primary: NAFLD, Hepatic steatosis attenuation, ALT, AST, Albumin, Bilirubin level • Weight, BMI, waist circumference, levels, lipid profile, glucose metabolism markers, and anthropometric parameters expressed as means and standard deviation	• Alcohol-induced hepatic steatosis, other chronic liver diseases such as cirrhosis • Parameters expressed qualitatively
Study design	• RCTs, cluster RCTs, pseudo-randomized controlled trial, non-randomised controlled clinical trials, cluster trials; case-control, prospective cohort studies.	• Controlled before-after studies, ITS studies without a control group, cross-sectional studies, pilot studies, case series, case reports, non-study-based sources, narrative reviews and systematic reviews. • Interrupted time-series studies with a control group, pilot study, retrospective cohort studies cross-sectional studies, nested case-control studies
Language	• English	• Other than English

Data extraction

After selecting eligible studies, different types of data were extracted, including author, year of publication, country, sample size, participants’ age, study design, intervention, outcomes, outcome measures, statistical analysis, and results. In the case of incomplete data, the authors of the articles were contacted via email. Given that the results of the biochemical variables were presented using different units of measurement, only data on patients who completed the studies were used for analysis. Liver histological outcomes (i.e., steatosis, lobular inflammation, hepatocellular ballooning, fibrosis), liver fat content assessed by imaging studies (i.e., ultrasonography, magnetic resonance imaging, or computed tomography) and levels of the liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were determined.

Quality Assessment

The quality of included studies was critically assessed in duplicates by the two reviewers (AD and YT) independently. The risk of bias was evaluated using the revised Cochrane risk of bias tool for randomised trials (RoB 2.0). Each journal article was assessed individually at the outcome level and scores as ‘low risk of bias’, ‘high risk of bias’ or classified as ‘some concerns’. In addition, the Joanna Briggs Institute (JBI) Critical Appraisal Checklists were used to assess the risk of bias assessment for studies other than case-control studies (20). The JBI tools are comprised of 9 to11 questions with options ‘yes’ indicating higher quality, ‘no’ indicating poor quality or ‘unclear.’ The overall appraisal allowed authors to ‘Include’ or ‘Exclude’ studies. Studies with ≥ 3 ‘no’ or ‘unclear’ categories were excluded (see Fig. 1).

Study selection

A total of 2786 records were obtained from the initial database search. After removing duplicates (n = 1913), 873 studies were screened by titles and abstracts based on inclusion and exclusion criteria. From these studies, 58 studies were retrieved for full-text screening. After careful review of these studies, a total of 36 studies (31 RCTs and 5 case-control studies) were included for quality assessment and data extraction. The study selection is detailed in the PRISMA flow diagram (Fig. 1).

Quality assessment

There was a total of 31outcomes from the RCTs (Table S3). The quality assessment showed that 19 studies had ‘low’ (16, 18, 19, 21–36), 10 studies had ‘some concerns’(15, 17, 37–44) and 2 studies had ‘high’ risk of bias(45, 46). Therefore, the overall quality of the evidence showed that around 61% of studies had high quality. On the other hand, 2 of 7 case-control studies had ≥ 3 ‘no’ or ‘unclear’ categories and were excluded (47, 48). Remaining 5 case-control studies were included in the current review(49–53) (Fig. 1 and Table S2).

Characteristics of included studies

The characteristics of the selected articles (n = 36) are summarised in Table 2. Most of the selected studies were conducted in Iran (n = 8)(15, 18, 19, 27, 35, 38, 44, 51), followed by China (n = 6)(23, 26, 32, 46, 50, 53) United States (n = 4)(21, 22, 30, 45), Italy (n = 3) (31, 37, 41), Australia (n = 2)(28, 42), Korea (n = 2) (33, 52), India (n = 2) (17, 49), Brazil (n = 1) (24), Greece (n = 1)(34), Germany (n = 1)(16), Mexico (n = 1)(43), Poland (n = 1)(39), Serbia (n = 1)(36), Spain (n = 1)(40), Sweden (n = 1) (25), and the United Kingdom (n = 1)(29). All studies were published between 2008 and 2021. The duration of the intervention ranged from 8 weeks to 104 weeks. In this systematic review, 1080 participants were in the intervention group and 1006 in the comparison group. Similarly, 1086 individuals were recruited as cases and 955 individuals were recruited as a control for case-control studies. The mean age of participants at baseline ranged between 36 and 59 years. The mean BMI at baseline ranged from 23.6 to 35.8 kg/m². Majority of studies recruited both men and women, except five studies assessed only men(16, 17, 19, 34, 36) and two studies assessed women (43, 50). Among 31 intervention studies, 5 studies used Mediterranean diet that is rich in MUFA, PUFA and low in SFA (34, 36, 40–42), 4 studies used hypocaloric diet with modified dietary fat (33, 38, 39, 43), 1 study used DASH regimen with reduced saturated fat and cholesterol (35), 6 studies used culinary fat (15–19, 44), 12 studies used n-3 PUFA supplements (21–27, 29–32, 45) and 2 studies offered diet plus n-3 PUFA supplements(37, 46). Both studies used the American Heart Association diet (37, 46). Also, 3 other studies advised participants to adhere hypocaloric diet or a heart-healthy diet (i.e., the American Heart Association Diet) (21–23).

Table 2

Characteristics of selected studies (n = 36)
Author (year)		Country	Sample size	Mean age (years)	Gender	Mean BMI (kg/m²)	Types of study	Intervention time
Arefhosseini (2011)(38)		Iran	Intervention n = 22 Control n = 22	Intervention: 38.0 ± 8.1 Control: 40.6 ± 8.3	M/F	Intervention: 81.75 ± 11.4 Control: 82.45 ± 11.90	Double- blinded randomised controlled trial	6 weeks
Argo (2015)(21)		USA	Intervention n = 17, Placebo n = 17	Intervention: 46.4 ± 12.1 Placebo: 47.2 ± 12.0	M/F	Intervention: 33.3 ± 8.0 Placebo: 31.6 ± 6.7	Double-blinded randomised placebo-controlled trial	52 weeks
Bhatt (2019) (49)		India	Cases:169, control:173	Cases: 38.3 ± 6.9 Control: 37.2 ± 7.0	M/F	Cases: 27.9 ± 2.7 Control 27.4 ± 3.2	Case-control	N/A
Cheng (2016)(50)		China	Cases:17, control:19	Cases: 43.5 ± 10.9 Control: 48.8 ± 12.2	F	Cases: 35.8 ± 4.5 Control: 26.8 ± 4.3	Case control	N/A
Dasarathy (2015)(22)		USA	Intervention n = 18, Placebo n = 19	Intervention: 51.5 ± 6.9 Placebo: 49.8 ± 12.1	M/F	Intervention: 34.5 ± 4.6 Placebo: 35.8 ± 6.6	Double-blinded randomised placebo-controlled trial	48 weeks
Entezari (2021)(51)		Iran	Cases:197 Control: 50	Cases: 44⋅07 ± 10⋅36 Control: 43⋅31 ± 12⋅15	M/F	Cases: 31⋅85 ± 4⋅12 Control: 25⋅40 ± 3⋅94	Case control	N/A
Han (2014) (52)		Korea	Cases:169 Control: 179	Cases: 44.6 Control: 38.8	M/F	Not reported	Case control	N/A
Jang (2018) (33)		Korea	Intervention: 52 Control: 54	Intervention: 43.6 ± 11.8 Control: 42.4 ± 3.0	M/F	Intervention: 27.4 ± 4.5 Control: 26.5 ± 3.3	Randomised controlled trial	8 weeks
Katsagoni (2018)(34)	Greece		Intervention: 21 Control: 21	Intervention Median: 44 (IQR: 41–60) Control: 47 (IQR: 42–60)	M	Intervention: Median 31.67 (IQR: 27·4–33·6) Control: 31.67 (IQR: 27·4–33·6)	Randomised, controlled single-blind clinical trial	24 weeks
Khonche (2019)(15)		Iran	Intervention: 60 Placebo: 60	46.64 ± 12.18	M/F	27 ± 2.1	Two-arm, randomized, double-blind, placebo controlled parallel group trial	12 weeks
Kruse (2020)(16)		Germany	Intervention n = 11 Control n = 15	Intervention: 58 ± 2.64 Control: 54 ± 3.95	M	Intervention: 32.0 ± 0.76 Control: 33.1 ± 1.44	Open labelled randomised controlled trial	8 weeks
Li (2015)(23)		China	Intervention n = 39, Placebo n = 39	Intervention:51.6 ± 6.6 Placebo: 50.4 ± 7.2	M/F	Intervention:28 ± 1.4 Placebo:27.2 ± 1.3	Double-blinded randomised placebo-controlled trial	24 weeks
Maciejewska (2018)(39)		Poland	N = 55	49.4 ± 13.3	M/F	32.6 ± 5.3	N/A	24 weeks
Marin- Alejandre, (2021)(40)		Spain	Intervention n = 58, Control n = 98	Intervention:51.1 ± 9.8 Placebo: 49.2 ± 8.9	M/F	Intervention:33.3 ± 4 Placebo:33.7 ± 4	Randomised-controlled trial	104 weeks
Misciagna (2017)(41)		Italy	Intervention n = 50, Control n = 48	N/A	M/F	N/A	Parallel-group randomized controlled clinical trial	24 weeks
Nigam (2014)(17)		India	olive oil (n = 30), canola oil (n = 33), and control oil (n = 30)	Olive oil: 37.2 ± 6.2 Canola oil: 38.0 ± 6.4 Control oil 36.2 ± 7.1	M	Olive oil: 27.2 ± 2.3 Canola oil:27.4 ± 5.7 Control oil: 27.4 ± 2.7	Randomized, parallel, open-label	24 weeks
Nogueira (2016)(24)		Brazil	Intervention n = 27 Placebo n = 23	Intervention: 52.5 ± 7.2 Placebo: 53.9 ± 6.8	M/F	Intervention: 31.1 ± 4.6 Placebo: 30.3 ± 4.4	Double-blinded randomised placebo-controlled trial	24 weeks
Oscarsson (2018) (25)		Sweden	Intervention n = 23 Placebo n = 23	Intervention 60 Placebo: 59.5	M/F	Intervention:30 Placebo: 29.7	Double-blinded randomised placebo-controlled trial	12 weeks
Properzi (2018)(42)		Australia	Intervention n = 26 Placebo n = 25	Intervention: 51.0 ± 13.36 Placebo: 53.0 ± 9.06	M/F	Intervention: 31.5 ± 4.1 Placebo: 30.2 ± 5.6	Prospective, parallel-group, single-blinded, randomized controlled trial	12 weeks
Qin (2015)(26)		China	Intervention n = 36 Placebo n = 34	Intervention: 46.0 ± 10.7 Placebo: 44.3 ± 10.9	M/F	Intervention:26.4 ± 3.9 Placebo:26.0 ± 2.8	Double-blinded randomised placebo-controlled trial	12 weeks
Rahmanabadi, (2019)(27)		Iran	Intervention n = 25 Placebo n = 25	Intervention: 40.3 ± 5.5 Placebo: 37.52 ± 9.7	M/F	Intervention:33.6 ± 3.7 Placebo:34.1 ± 4.5	Double-blinded randomised placebo-controlled trial	12 weeks
Razavi (2016)(35)		Iran	Intervention:27 Control:27	Intervention: 39.7 ± 7.3 Control: 42.8 ± 10.6	M/F	Intervention: 28.5 ± 3.2 Control: 28.3 ± 3.3	Two-arm parallel randomized controlled clinical trial	8 weeks
Rezaei (2019)(18)		Iran	Intervention: 26 Control: 28	Intervention: 46.3 ± 13.6 Control: 40.8 ± 8.7	M/F	Intervention: 30.6 ± 3.6 Control: 29.6 ± 3.9	Randomized, double-blind, parallel-group, controlled, clinical trial	12 weeks
Rezaei (2020)(19)		Iran	Intervention: 29 Control: 28	Intervention: 45.5 ± 8.7 Control: 40.8 ± 8.7	M	Intervention: 30.1 ± 4.1 Control: 29.6 ± 3.9	Randomised, double-blind, placebo-controlled clinical trial	12 weeks
Ristic-Medic (2020)(36)		Serbia	Intervention: 12 Control: 12	Intervention: 34.4 ± 4.7 Control: 32.9 ± 3.8	M	Intervention: 30.4 ± 1.8 Control: 30.2 ± 2.3	Randomised control trial	12 weeks
Rodríguez-Hernández (2011)(43)		Mexico	Intervention: 28 Control: 26	Intervention: 45.0 ± 9.1 Control: 46.3 ± 9.1	F	Intervention: 36.9 ± 6.8 Control: 38.7 ± 6.1	Non-controlled clinical intervention study	24 weeks
Ryan (2013)(28)		Australia	Intervention n = 6 Control n = 6	55.0 ± 14.0	M/F	32.0 ± 4.2	Randomised cross-over trial	12 weeks
Sanyal (2014)(45)		USA	Intervention n = 168 Placebo n = 75	Intervention: 47.8 ± 11.8 Placebo: 50.5 ± 12.5	M/F	Intervention:35.5 ± 6.5 Placebo:33.6 ± 5.9	Double-blinded three-armed randomised placebo-controlled trial	52 weeks
Scorletti (2014)(29)		UK	Intervention n = 46 Placebo n = 45	Intervention: 48.6 ± 11.1 Placebo: 54.0 ± 9.6	M/F	Intervention:34.3 Placebo:32	Double-blinded randomised placebo-controlled trial	65–78 weeks
Shidfar (2018)(44)		Iran	Intervention n = 25 Placebo n = 28	Intervention: 46.14 ± 8.44 Placebo: 45.68 ± 10.8	M/F	Intervention: 29.64 ± 3.93 Placebo: 29.9 ± 3.77	Randomized, single-blind trial	12 weeks
Sofi (2010)(31)		Italy	Intervention: 11 Placebo: 11	Intervention: 55.0 Placebo: 54.0	M/F	Intervention:29.3 ± 4.1 Placebo: 29.3 ± 3.9	Randomised controlled trial	52 weeks
Song (2020)(32)		China	Intervention: 21 Placebo: 21	Intervention: 46.0 ± 5.0 Placebo: 47.0 ± 6.0	M/F	Intervention: 29.4 ± 3.4 Placebo:27.9 ± 2.4	Double-blind placebo-controlled clinical trial	12 weeks
Spadaro (2008)(37)		Italy	Intervention n = 18 Placebo n = 18	Intervention: 50.2 Placebo: 51.3	M/F	Intervention:30.1 Placebo:31	Double-blinded randomised placebo-controlled trial	24 weeks
Tobin (2018)(30)		USA	Intervention n = 60 Placebo n = 60	Intervention: 55.3 Placebo: 55.1	M/F	Intervention:32.1 Placebo:32.4	Double-blinded randomised placebo-controlled trial	24 weeks
Xie (2021)(53)		China	Cases = 534 Control = 534	Not reported	M/F	Not reported	Retrospective case-control	N/A
Zhu (2008)(46)		China	Intervention n = 66 Placebo n = 68	Intervention: 45 Placebo: 44	M/F	Intervention:26.4 Placebo:26	Double-blinded randomised placebo-controlled trial	24 weeks

In terms of sources of n-3 PUFA supplementation, 4 studies used fish oil (21, 22, 26, 32), 1 study used seal oil(46), 2 studies used eicosapentaenoic acid (EPA) or EPAþDHA ethyl ester (29, 45), 1 study used n-3 PUFA rich olive oil (31) and 2 studies did not specify the source of the oil (23, 37).

All the case-control studies (n = 5) examined the effects of total fat, saturated fat acid (SFA), monounsaturated fatty acid (MUFA), polyunsaturated fatty acids (PUFA) including n-3 and n-6 PUFAs intake on NAFLD (49–53). Of these, three studies used a food frequency questionnaire (49, 50, 53), one with the addition of a 24-hour dietary recall (49), and the other study used a 24-h recall and 4-day food records (52) (Table 3).

Table 3

Summary of the case-control studies included in the systematic review (n = 5)
Author (year)	Exposure	Adherence Assessment	Outcome	Outcome measurement	Result (Multivariate analysis)
Bhatt (2019) (49)	Total fat, MUFA, SFA, n-3 PUFAs, n-6 PUFAs	Food frequency questionnaire and 24-h dietary recall	NAFLD	Ultrasonographic assessment	Dietary fats (%) OR: 13.4 (95% CI: 4.6–39.3); p < 0.01
Cheng (2016)(50)	Total fat, MUFA, SFA, PUFA	Food frequency questionnaire	Hepatic lipid content	Radiologic assessment	Total fat (g) Hepatic fat fraction β: 0.36; p < 0.05 Intrahepatic lipid β: 0.42;p < 0.05
					SFA (g) Hepatic fat fraction β: 0.45; p < 0.05 Intrahepatic lipid β: 1.16; p < 0.05
					MUFA (g) Hepatic fat fraction β: -0.39; p > 0.05 Intra-0.51; p > 0.05
					PUFA (g/d) Hepatic fat fraction β: -1.19; p > 0.05 Intrahepatic lipid β: -1.10; p > 0.05
Entezari (2021)(51)	MUFA/PUFA ratio	Food frequency questionnaire	NAFLD	Ultrasonographic assessment	OR: 0⋅42 (95% CI 0⋅20 − 0⋅87); p < 0.01
Han (2014) (52)	SFA, PUFA, MUFA	24-h recall and 4-day food records	NAFLD	Ultrasonographic assessment	Dietary fats (%) Men Highest tertile < 22.5: OR: 1.13 (95% CI: 0.42–3.0); p > 0.05 Middle tertile 22.5–27.1: OR: 1.16 (95% CI 0.48, 2.78); p for trend > 0.05 Women Highest tertile < 23.5: OR: 0.93 (95% CI: 0.32–2.68) Middle tertile 23.5–28.4 mg/d: OR: 0.87(95% CI: 0.32–2.36) P for trend > 0.05
					n-3PUFA mg/d Men Highest tertile < 0.93 mg/d: OR: 2.16 (95% CI: 0.86–5.42) Middle tertile 0.93–1.63 mg/d: OR: 1.57(95% CI: 0.61–4.04) P for trend < 0.05 Women Highest tertile < 0.7mg/d: OR: 1.17 (95% CI: 0.46–2.94) Middle tertile 0.7–1.1 mg/d: OR: 1.23(95% CI: 0.481–3.15) P for trend > 0.05
					n-6/3 ratio NAFLD Men Highest tertile (T1) < 4.5): OR: 0.50 (95% CI: 0.2–1.3) Middle tertle (T2) 4.5–8.7 OR: 0.87 (95% CI: 0.37–2.06) P for trend > 0.05 Women Highest tertile (T1) < 5.7): OR: 0.70 (95% CI: 0.28–1.75) Middle tertle (T2) 5.7–9.1 OR: 0.81 (95% CI: 0.36–1.82) P for trend > 0.05
Xie (2021)(53)	Total PUFA	Semiquantitative food frequency questionnaire	NAFLD	Ultrasonographic assessment	OR: 1.18 (95% CI: 1.13, 1.23); p < 0.0001

Outcomes

Effects of dietary fat and fatty acids on NAFLD

Case control studies

The effects of dietary fatty acid intake on NAFLD were evaluated in 5 case-control studies (49–53) (Table 3). Of the 5 studies, one study showed a positive association between total fat intake and the risk of NAFLD (49). This study did not report the effects of saturated, monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) on NAFLD(49). The authors were contacted to obtain the data, but the necessary data was not provided(49). Another study by Cheng et al. showed a positive association between total fat and saturated fatty acid intake and hepatic fat content (50). While no associations were observed between MUFA or PUFA and NAFLD(50). Entezari et al. observed that the highest MUFA/SAFA ratio tertiles (> 0.57) have lower odds for NAFLD in crude (OR: 0⋅47, 95% CI: 0⋅24–0⋅95) and multivariable adjustment (OR: 0.42, 95% CI: 0.20–0.87) (51). Furthermore, a recent study by Xie et al. showed a positive association between total PUFA intake (18.8–29.3 g/day) and the risk of NAFLD among Chinese adults(53). Further analysis (total PUFA intake to energy intake ratio) also showed that the risk of NAFLD increased as total PUFA intake to energy intake ratio increased (OR:1.14, 95% CI: 1.08–1.20)(53). In contrast, Han et al. showed that lower intake of n-3 PUFA was significantly associated with an increased risk of NAFLD in men (52).

Effects of dietary fat on histologic parameters and liver fat content

RCTs

The effect of hypocaloric diets with modified dietary fat assessed in 4 RCTs (33, 38, 39, 43) (Table 4), however, no effects were observed in liver histology. The effect of the Mediterranean dietary pattern that is low SFA and high PUFA and MUFA on NAFLD was evaluated in 6 RCTs (28, 34, 36, 40–42). Of 6 studies, 2 studies showed a significant reduction in liver stiffness (34, 40), 2 studies reported a significant reduction in liver fat (28, 40), 1 study reported a significant reduction in liver enzyme level (36) and 1 study reported a significant reduction in NAFLD score assessed by ultrasonography (41). Interestingly, the effects intervention varies from 12 weeks to 104 weeks (28, 34, 40). In addition, liver stiffness was measured using ultrasonography (34) and fibro scan (40). Similarly liver fat was measured by magnetic resonance imaging (28, 40).

Table 4

Summary of the clinical trials included in the systematic review (n = 31)
Author (year)	Intervention			Outcomes	Outcome measurement	Outcome result
Author (year)	Intervention	Control/Placebo		Outcomes	Outcome measurement	Outcome result
Dietary fat and fatty acids
Arefhosseini (2011)(38)	Hypocaloric diet: 55% Carbohydrate, 25% fat and 20% protein		Hypocaloric diet: 40% Carbohydrate, 40% fat and 20% protein	Ultrasonographic measure: Steatosis Grade	MD control minus intervention group	-1.0; p > 0.05
Arefhosseini (2011)(38)	Hypocaloric diet: 55% Carbohydrate, 25% fat and 20% protein		Hypocaloric diet: 40% Carbohydrate, 40% fat and 20% protein	Biochemical assessment: ALT (U/L), AST (U/L)	MD control minus intervention group	ALT: -0.09; p > 0.05 AST: − 1.76; p > 0.05
Jang (2018)(33)	Hypocaloric diet: 60–70% Carbohydrate, 15–20% fat, 15–20% protein		Hypocaloric diet: 50–60% Carbohydrate, 20–25% fat, 20– 25% protein	CT scan: Liver-to-spleen ratio	MD control minus intervention group	Not different; p > 0.05
Jang (2018)(33)				Biochemical assessment: ALT (U/L), AST (U/L)	MD control minus intervention group	ALT: 22.77; p < 0.05 AST: 6.8; p > 0.05
Katsagoni (2018)(34)	Mediterranean Diet: 45% Carbohydrates, 15% protein, 35% fat, 20% MUFA, 8% PUFA, 7% SFA; Main source of fat was olive oil.		45% Carbohydrates, 15% protein, 35% fat, 20% MUFA, 8% PUFA, 7% SFA	Non-invasive methods: NAFLD fibrosis score	MD (95% CI) control minus intervention group	−0.15 (− 0.70, 0.40); p > 0.05
				Ultrasonographic measure: Liver stiffness (kPa)	MD (95% CI) control minus intervention group	−0.83 (− 0.70, − 0.98); p < 0.05
				Biochemical assessment: ALT (U/L), AST (U/L)	MD (95% CI) control minus intervention group	ALT: −0.79 (− 0.57, 1.1); p > 0.05 AST: not reported
Maciejewska, (2018)(39)	55–65% Carbohydrate, 20–30% fat (olive oil and rapeseed oil as main sources), 1.0 g/kg of body mass/ day protein.		None	Biochemical assessment: ALT (U/L), AST (U/L)	MD before minus after intervention	ALT: 4.6; p < 0.01 AST: 15.8; p < 0.01
Marin- Alejandre, (2021)(40)	Mediterranean Diet: 40%- 45% carbohydrates, 30%- 35% fats (favouring extra virgin olive oil and n-3 PUFA) and 25% proteins		55% carbohydrates, 30% fats with a healthy fatty acid profile and 15% proteins	Ultrasonographic measure: Steatosis degree	MD control minus intervention group	Baseline vs 52 weeks: -0.4; p > 0.05 Baseline vs 104 weeks: -0.4; p > 0.05
				Radiologic assessment: Liver fat (%)	MD control minus intervention group	Baseline vs 52 weeks: 0.9; p > 0.05 Baseline vs 104 weeks: -1.9; p < 0.05
				Fibro Scan: Liver stiffness (kPa)	MD control minus intervention group	Baseline vs 52 weeks: 0.5; p > 0.05 Baseline vs 104 weeks: -9.5; p < 0.05
				Biochemical assessment: ALT (IU/L), AST (IU/L)	MD control minus intervention group	ALT Baseline vs 52 weeks: -1.5; p > 0.05 Baseline vs 104 weeks: -0.5; p > 0.05 AST Baseline vs 52 weeks: -2.9; p > 0.05 Baseline vs 104 weeks: 0.7; p > 0.05
Misciagna (2017)(41)	Low Glycemic Index Mediterranean Diet: 50% Carbohydrate, 30% fat (< 10% saturated fat, and MUFA and PUFA from olive oil, plant and marine sources) and 20% protein		40% Carbohydrate, 35–40% fat (< 10% saturated fat) and 20% protein	Ultrasonographic measure: NAFLD	MD (95% CI) control minus intervention group, without exact values but p-value provided	Significantly different; p < 0.05
Properzi (2018)(42)	Mediterranean Diet: 40% Carbohydrate, 35%– 40% fat (with < 10% of saturated fat), 20% protein + 750g nuts (almonds or walnuts) and 750 ml olive oil		50% Carbohydrate, 30% fat (with < 10% of saturated fat), 20% protein + 1kg muesli and 200g low fat snack bars	Magnetic resonance spectroscopy: Liver fat (%)	MD control minus intervention group	-4.0; p > 0.05
				FibroScan: Liver stiffness (kPa)	MD control minus intervention group	0.4; p > 0.05
				Biochemical assessment: HepaScore (kPa) (ALT (IU/L)	MD control minus intervention group	-0.01; p > 0.05 ALT: -6; p > 0.05
Razavi (2016)(35)	DASH diet 52–55% Carbohydrate, 30% fat (reduction of saturated fat and cholesterol), 16–18% protein		52–55% Carbohydrate, 30% fat (higher saturated fat and cholesterol), 16–18% protein	Ultrasonographic measure: Steatosis Grade	MD control minus intervention group	Grade I: 3; p > 0.05 Grade II: 5; p > 0.05
Razavi (2016)(35)				Biochemical assessment: ALT (IU/L), AST (IU/L)	MD control minus intervention group	ALT: − 4.6; p < 0.05 AST: 9.1; p > 0.05
Ristic-Medic (2020)(36)	Mediterranean Diet: 50% Carbohydrate, > 30% fat (< 8% saturated fat), 15% protein, 15% MUFA, > 5% PUFA. Main source of fat was olive oil ≥ 4 tablespoons /day		60% Carbohydrate, ≤ 25% fat (< 10% saturated fat), 15% protein, > 10% MUFA, > 5% PUFA. Main source of fat was olive oil > 4 tablespoons/day. Vegetable oils (including olive oil) ≤ 2 tablespoons/day	Ultrasonographic measure: Steatosis Index	MD control minus intervention group	-0.08; p > 0.05
				Biochemical assessment: ALT (IU/L), AST (IU/L)	MD control minus intervention group	ALT: -6.22; p > 0.05
				Biochemical assessment: ALT (IU/L), AST (IU/L)	Median difference control minus intervention group	AST: -2.35; p < 0.05
Rodríguez-Hernández (2011)(43)	54% Carbohydrate, 21% fat (< 10% saturated fat), 25% protein		45% Carbohydrate, 28% fat, 27% protein	Biochemical assessment: ALT (U/L), AST (U/L)	MD control minus intervention group	ALT: 6.5; p > 0.05 AST: 5.8; p > 0.05
Ryan (2013)(28)	Mediterranean Diet: 40% Carbohydrate, 40% fat (MUFA and n-3-PUFA from plant and marine sources) and 20% protein		50% Carbohydrate 30% fat (n-6-PUFAs) and 20% protein	Liver histology: Intrahepatic fat	MD control minus intervention group	-4.40; p < 0.03
Ryan (2013)(28)			50% Carbohydrate 30% fat (n-6-PUFAs) and 20% protein	Biochemical assessment: ALT (IU/L)	MD control minus intervention group	Not different; p > 0.05
Cooking oil
Khonche (2019)(15)	5 ml Nigella sativa seed oil (rich in MUFA and PUFA)		Placebo oil	Ultrasonographic measure: steatosis	MD control minus intervention group; without exact values but p-value provided	Grade of hepatic steatosis significantly reduced in nigella sativa oil group; p < 0.05
Khonche (2019)(15)	5 ml Nigella sativa seed oil (rich in MUFA and PUFA)		Placebo oil	Biochemical assessment: ALT (U/L), AST (U/L)	MD control minus intervention group	ALT: − 18.4; p < 0.001 AST: − 17.1; p < 0.001
Kruse (2020)(16)	50g/ day Refined rapeseed, containing high amounts of alpha linolenic acid		Refined olive oil	MRI: Intrahepatic fat content (%)	MD control minus intervention group	-4.4; p < 0.05
Kruse (2020)(16)			Refined olive oil	Biochemical assessment: ALT (U/L), AST (U/L)	MD control minus intervention group	ALT: -1.6; p > 0.05 AST: 0.87; p > 0.05
Nigam (2014)(17)	55–70% carbohydrate, 20% fat (Canola oil or olive oil as a cooking medium ≤ 20 g/day) and 15–21% protein.		55–70% carbohydrate, 20% fat Refined oil (soybean or safflower that composed of 12–16% SFAs, 15–24% MUFAs and 50–60% PUFAs as a cooking medium ≤ 20 g/day) and 15–21% protein.	Ultrasonographic measure: Steatosis	Olive oil: MD control minus intervention group, without exact values but p-value provided	Steatosis grade II: Significantly different; p < 0.01
				Ultrasonographic measure: Steatosis	Canola oil: MD control minus intervention group, without exact values but p-value provided	Significantly different; p < 0.01
				Biochemical assessment: ALT (U/L), AST (U/L)	Olive oil: MD control minus intervention group	ALT: -1.0; p > 0,05 AST: − 2.1; p > 0.05
				Biochemical assessment: ALT (U/L), AST (U/L)	Canola oil: MD control minus intervention group	ALT: -1.7; p > 0.05 AST: -3.6; p > 0.05
Rezaei (2019)(18)	50–55% Carbohydrate, 30–35% fat (20 mL of olive oil), 10–15% protein		50–55% Carbohydrate, 30–35% fat (20 mL of sunflower oil), 10–15% protein	Ultrasonographic measure: Steatosis	MD control minus intervention group	-0.46; p < 0.001
Rezaei (2019)(18)				Biochemical assessment: ALT (U/L), AST (U/L)	MD control minus intervention group	ALT: 2.8; p > 0.05 AST: 1.2; p > 0.05
Rezaei (2020)(19)	50–55% Carbohydrate, 30–35% fat (20 mL of flaxseed oil), 10–15% protein		50–55% Carbohydrate, 30–35% fat (20 mL of sunflower oil), 10–15% protein	Ultrasonographic measure: Steatosis	MD control minus intervention group	-0.38; p < 0.01
Rezaei (2020)(19)				Biochemical assessment: ALT (U/L), AST (U/L)	MD control minus intervention group	ALT: 1.0; p > 0.05 AST: 0.9; p > 0.05
Shidfar (2018)(44)	50% Carbohydrate, 20% fat (olive oil and 10% from other sources, dairy, meats, and nuts) and 20% protein		50% Carbohydrate, 30% fat (culinary fat and 10% from other sources, dairy, meats, and nuts) and 20% protein	Ultrasonographic measure: Steatosis	MD control minus intervention group	-2.0; p > 0.05
Shidfar (2018)(44)				Biochemical assessment: ALT (IU/dl), AST (IU/dl)	MD control minus intervention group	ALT: -7.65; p < 0.01 AST: -6.03; p < 0.01
Fatty acids supplement
Argo (2015)(21)	Hypocaloric diet + n-3 PUFA: 3000 mg/day		Soybean oil and small amounts of fish and lemon oils (only 8% n-3)	Histologic assessment: Steatosis score, lobular inflammation score, NAS score, ballooning score, fibrosis score	MD (95% CI) control minus intervention group, without exact values but p-value provided	Steatosis score: not different; p > 0.05 Lobular inflammation: not different; p > 0.05 NAS: not different; p > 0.05 Ballooning score: not different; p > 0.05 Fibrosis score: not different; p > 0.05
				Radiologic assessment: Hepatic fat	MD (95% CI) control minus intervention group, without exact values but p-value provided	Hepatic fat content: significantly different; p < 0.001
				Biochemical assessment: ALT (U/L), AST (U/L)	MD (95%CI) control minus intervention group, without exact values but p-value provided	ALT: not different; p > 0.05 AST: not different; p > 0.05
Dasarathy, S., (2015) (22)	Heart healthy diet + 2160 mg of EPA and 1440 mg of DHA		Corn oil	Histologic assessment: Steatosis grade, lobular inflammation grade, ballooning grade, fibrosis grade	MD of control minus intervention group	Steatosis: 0.36; p < 0.05 Lobular inflammation: -0.43; p < 0.001 NAS: 1.01; p < 0.001 Ballooning score: 0.07; p > 0.05 Fibrosis score: -0.06; p > 0.05
Dasarathy, S., (2015) (22)	Heart healthy diet + 2160 mg of EPA and 1440 mg of DHA		Corn oil	Biochemical assessment: ALT (IU/dl), AST (IU/dl)	MD of control minus intervention group	ALT: 2.7; p > 0.05 AST: 6.2; p > 0.05
Li, Y.H., (2015) (23)	Low-fat, low-cholesterol, and low carbohydrate diets + 50 mL PUFA with 1:1 ratio of EHA and DHA		Saline	Histology measure: Steatosis, necro-inflammatory grade, fibrosis stage and ballooning	MD of control minus intervention group	Steatosis: -0.5; p < 0.001 Necro-inflammatory grade: 0.4; p < 0.05 Fibrosis stage:- 0.5; p < 0.001 Ballooning: -0.6; p < 0.001
Li, Y.H., (2015) (23)			Saline	Biochemical assessment: ALT (U/L), AST (U/L)	MD of control minus intervention group	ALT: -10.5; p < 0.001 AST: -16.3; p < 0.001
Nogueira, M.A., (2016) (24)	3 n-3 PUFA capsules/day (0.945g)		2 ml of mineral oil	Histology measure: Steatosis, necro-inflammatory grade, fibrosis stage and ballooning	MD control minus intervention group	Steatosis score: 0.1 (-0.1); p > 0.05 Lobular inflammation: not different; p > 0.05 NAS:0.16 (-0.5); p > 0.05 Ballooning score: 0.1; p > 0.05 Fibrosis score: not different; p > 0.05
Nogueira, M.A., (2016) (24)	3 n-3 PUFA capsules/day (0.945g)		2 ml of mineral oil	Biochemical assessment: ALT (U/L), AST (U/L)	MD control minus intervention group	ALT: 12.2;p < 0.05 AST: 10.4; p < 0.01
Oscarsson, J., (2018) (25)	Fenofibrate 200mg / OM-3CA 4g (> 850mg PUFA; 500-600mg EPA + 150-250mg, DHA10-80mg DPA)		Placebo	Radiologic assessment: Liver proton density fat fraction Total liver volume Total liver fat volume	MD of control minus intervention groups	Liver proton density fat fraction OM-3CA: 0.15; p > 0.05 Fenofibrate: -1.88; p > 0.05 Total liver volume OM-3CA: not different; p > 0.05 Fenofibrate: -0.04; p > 0.05 Total liver fat volume OM-3CA: not different; p > 0.05 Fenofibrate: -0.05; p > 0.05
Oscarsson, J., (2018) (25)			Placebo	Biochemical assessment: ALT (U/L), AST (U/L)	MD of control minus intervention groups	ALT OM-3CA: -0.11; p > 0.05 Fenofibrate: -0.06; p > 0.05 AST OM-3CA: -0.07; p > 0.05 Fenofibrate: -0.07; p > 0.05
Qin, Y., (2015) (26)	Two fish oil Capsules - twice/day (each capsule contained 182 mg of EPA and 129 mg of DHA)		Two corn oil capsules twice/day	Biochemical assessment: ALT (IU/L), AST (IU/L)	MD of control minus intervention groups	ALT: -8.8; p > 0.05 AST: 5.4; p > 0.05
Rahmanabadi, A., (2019) (27)	Two 1200 mg α-LA capsules/day (each containing 600 mg R.S-α-LA)		Corn flour	Ultrasonographic measure: Steatosis score	MD (95% CI) control minus intervention group, without exact values but p-value provided	Not different; p > 0.05
Rahmanabadi, A., (2019) (27)			Corn flour	Biochemical assessment: ALT (IU/L), AST (IU/L)	MD (95% CI) control minus intervention group, without exact values but p-value provided	ALT: Not different; p > 0.05 AST: Not different; p > 0.05
Sanyal, A. J., (2014) (45)	EPA-E - 1800 mg/d or EPA-E − 2700 mg/d		Placebo	Histologic assessment: Steatosis score, lobular inflammation score, NAS score, ballooning score, fibrosis score	Median difference control minus intervention groups	Steatosis score EPA-E 1800 mg/d: 0; p > 0.05 EPA-E 2700 mg/d: 0; p > 0.05 Lobular inflammation EPA-E 1800 mg/d: 0; p > 0.05 EPA-E 2700 mg/d: 0; p > 0.05 NAS EPA-E 1800 mg/d: -1;p > 0.05 EPA-E 2700 mg/d: -1;p > 0.05 Ballooning score EPA-E 1800 mg/d:0.5; p > 0.05 EPA-E 2700 mg/d: 0; p > 0.05 Fibrosis score EPA-E 1800 mg/d: 0; p > 0.05 EPA-E 2700 mg/d: 0; p > 0.05
Sanyal, A. J., (2014) (45)	EPA-E - 1800 mg/d or EPA-E − 2700 mg/d		Placebo	Biochemical assessment: ALT (IU/L), AST (IU/L)	Median difference control minus intervention groups	ALT EPA-E 1800 mg/d: -5.5; p > 0.05 EPA-E 2700 mg/d: -5.5; p > 0.05 AST EPA-E 1800 mg/d: -6.5; p > 0.05 EPA-E 2700 mg/d:-2; p > 0.05
Scorletti, E. (2014) (29)	Omacor 4g/day (1 g contains 460 mg of EPA and 380 mg of DHA) 4g/day		Olive oil 4 g/day	Histologic assessment: Fibrosis score	MD control minus intervention groups	Fibrosis: -0.1; p > 0.05
				Radiologic assessment: Liver fat percentage	MD control minus intervention groups	Liver fat percentage: -3.0; p > 0.05
				Biochemical assessment: ALT (IU/L), AST (IU/L)	MD control minus intervention groups	ALT: 6; p > 0.05 AST: -0.2; p > 0.05
Sofi et al, (2010) (31)	0.83 g/day olive oil with enriched n-3 PUFA (0.47g EPA and 0.24g DHA)		Olive oil	Ultrasonographic measure: Steatosis score	MD control minus intervention group	Steatosis score: -0.04; p < 0.05
Sofi et al, (2010) (31)			Olive oil	Biochemical assessment: ALT (IU/L), AST (IU/L)	MD control minus intervention group	ALT: -7.3; p > 0.05 AST: -17.4; p = 0.05
Song (2020)(32)	Fish oil capsule (450 mg EPA + 1500 mg DHA)		Soymilk powder + placebo capsule	Radiologic assessment: Liver Steatosis	MD control minus intervention group	Steatosis score: -0.44; p > 0.05
Song (2020)(32)	Fish oil capsule (450 mg EPA + 1500 mg DHA)		Soymilk powder + placebo capsule	Biochemical assessment: ALT (U/L), AST (U/L)	MD control minus intervention group	ALT: -0.17; p > 0.05 AST: -2.97; p > 0.05
Spadaro, L., (2008) (37)	American Heart Association diet + 1 g PUFAs twice/ day		American Heart Association diet	Ultrasonographic measure: Steatosis score	MD control minus intervention group	Steatosis score: -1.22; p < 0.001
Spadaro, L., (2008) (37)	American Heart Association diet + 1 g PUFAs twice/ day		American Heart Association diet	Biochemical assessment: ALT (U/L), AST (U/L)	MD control minus intervention group	ALT: -12.9; p < 0.05 AST: 04.6; p < 0.05
Tobin, D., (2018) (30)	American Heart Association diet + n-3 PUFA 1g (460 mg EPA + 380 mg DHA)		Olive oil	Radiologic assessment: Liver fat percentage	MD control minus intervention group	Liver fat percentage: -1.6; p > 0.05
Tobin, D., (2018) (30)			Olive oil	Biochemical assessment: ALT (U/L), AST (U/L)	MD control minus intervention group	ALT: 5.2; p < 0.05 AST: 0.3; p < 0.05
Zhu, F. S., (2008) (46)	American Heart Association diet + 2 g n-3 PUFA seal Oils three times/day		American Heart Association diet + 2 g placebo three times/day	Ultrasonographic measure: Steatosis score	MD control minus intervention group	Steatosis score: -0.41; p < 0.001
Zhu, F. S., (2008) (46)				Biochemical assessment: ALT (U/L), AST (U/L)	MD control minus intervention group	ALT: 13.9; p < 0.01 AST: 12.2; p < 0.01
MD: Mean difference; βD: β difference

Furthermore, of the 6 studies that evaluated the effects of culinary fats, 4 studies reported that the consumption of culinary fats which are high in MUFA, n-3 and n-6 PUFA had positive effects in reducing liver steatosis as measured by ultrasound (15, 17–19). These studies observed a significant reduction in liver steatosis after using 20ml or less MUFA and PUFA rich oil for 12–24 weeks (15, 17–19).

Effects of dietary fat on liver enzymes

The effect of low-fat diets on liver enzyme was inconclusive (Table 4). A study by Jang et al. reported a significant reduction of serum ALT in control group compared to low fat diet group after 8-week of intervention (33). Only 1 study that used the Mediterranean diet, reported a significant reduction in AST level (36). Another study by Razavi et al. observed a significant reduction in ALT level with a Dietary Approaches to Stop Hypertension (DASH) diet (35). Maciejewska et al. observed that a hypocaloric diet with modified fat for 24-weeks resulted a significant reduction of serum ALT and AST (39).

Similarly, 2 studies found significant reductions in ALT and AST using cooking oil rich in MUFA and n-6 PUFA (15, 44). These studies used nigella sativa oil and olive oil for 12 weeks (15, 44).

Effects of n-3PUFA supplementation on histologic parameters

The effect of n-3 PUFA supplementation on NAFLD on liver fibrosis score, hepatocellular ballooning score, steatosis score, lobular inflammation score, or the NAFLD activity score using histologic assessment was examined in 6 studies (21–24, 29, 45) (Table 4). There were inconclusive effects on histological parameters with a very low certainty of evidence. Only Li et al. showed a significant improvement in steatosis score, necro-inflammatory score, fibrosis score and hepatocellular ballooning score with 50 mL/day n-3 PUFA supplementation for 24 weeks(23). While in the study by Dasarathy et al. reported a significant improvement in hepatic steatosis and lobular inflammation aggravated in placebo group, but no improvement observed in intervention group (22). Other studies found no improvements in any histological parameters (21, 24, 29, 45).

Effects of n-3 PUFA supplementation on liver fat content

The effects of n-3 PUFA supplementation on liver fat content, using MRI or MRS, were evaluated in 4 studies (21, 25, 29, 46) (Table 4). Only Argo et al. reported a significant reduction of hepatic fat content with 3000mg/d n-3 PUFA supplementation at 52 weeks (21). However, this study did not report post-intervention liver fat content values in the article(21). The remaining 3 studies did not reveal any significant changes in liver fat levels after the PUFA n-3 intervention (25, 29, 46). There was no effect of n-3 PUFA supplementation on liver fat content. The certainty of evidence of this outcome at different timepoint was very low.

Effects of n-3 PUFA supplementation on steatosis score assessed by ultrasonography

The effect of n-3 PUFA supplementation on steatosis score was evaluated in 5 studies (27, 31, 32, 37, 46) (Table 4). Most studies reported an improvement of steatosis score with n-3 PUFA supplementation compared to control group. Two of these studies assessed the effect of the supplement at 24 weeks(37, 46) and one study investigated the effect of the intervention at 52 weeks(31). Whereas two studies found no effect of n-3 PUFA supplementation on steatosis at 12 weeks (27, 32). The consumption n-3 PUFA supplementation had a beneficial effect on steatosis evaluated by ultrasonography. The certainty of evidence was high.

Effects of n-3 PUFA supplementation on liver enzymes

The effects of n-3 PUFA on serum ALT and AST were examined in 14 studies (21–27, 29–32, 37, 45, 46) (Table 4). Of them 5 studies found a significant improvement in ALT and AST in intervention groups compared to control groups (23, 24, 30, 37, 46). It should be noted that the improvement in liver enzyme levels was observed after 24 weeks of PUFA n-3 supplementation (23, 24, 30, 37, 46). The remaining studies found no significant change in liver enzyme levels after intervention(23, 24, 30, 32, 37, 46). Therefore, the effect of n-3 PUFA supplementation on liver enzyme was inconclusive and the certainty was low.

The current systematic review presents a relatively comprehensive summary of the existing evidence on the effects of fatty acids on liver-related outcomes through histologic, radiologic, ultrasonographic and biochemical assessments in adults with NAFLD. The screening stages resulted in 36 studies, which comprised 31 RCTs (21–27, 29–31, 37, 45, 46) and 5 case-control studies(49–53). The results of this study are heterogenous and showed some similarities and differences with previous systematic reviews and meta-analyses, indicating the need for further study.

Effects of total dietary fat and fatty acids on NAFLD

There was inconclusive evidence for the effects of dietary fat on NAFLD. In this review, we evaluated the effects of almost all fats, diets with modified amount of fats and culinary fats. All the included studies were not directly comparable due to the variation of dietary intake measures, outcome measures, duration of intervention, quantity of fatty acids and ethnicity. In line with our review, a previous systematic review and meta-analysis also showed that there was no effect of fat modified diets on NAFLD (1).

Findings from included studies indicated that the consumption of Mediterranean diet rich in MUFA, PUFA and low in SFA may have a beneficial effect on hepatic fat and stiffness. However, the duration of intervention was heterogenous. Likewise, a recent systematic review of RCTs indicated that the Mediterranean diet may be beneficial for reducing hepatic fat content, while the duration of the intervention ranged between 6 to 24 weeks (54). While, a systematic review by Saeed et al. described a significant reduction of liver steatosis with a Mediterranean diet that is rich in PUFA, however, the duration of the intervention varied (55). Mediterranean diet is mainly supplemented with extra virgin olive oil, avocados, nuts, and oily fish including salmon and sardines, which are high in n-3 PUFA. Olive oil is the primary source of recommended fat, replacing other oils and fats. The major fatty acid in olive oil is MUFA (i.e., oleic acid, 65–79%). However, the Mediterranean diet contains bioactive compounds, such as polyphenols and phytosterols, which makes it difficult to isolate the effects of MUFA and n-3 PUFA in Mediterranean diet on NAFLD.

Further, using of cooking oil namely olive, canola or flax seed oil has been shown to reduce liver steatosis (15, 17–19). Flaxseed oil is rich in n-3 PUFA, while olive oil is rich in MUFA and canola oil is rich in n-6 PUFA (56, 57). Since olive oil can reduce the accumulation of liver fat independently of metabolic pathways, likely through increased oxidation of fatty acids [Ref]. To date, there is no study has compared the effects of n-3 and n-6 PUFA on NAFLD. However, it would be difficult to isolate the nutritional effects of n-3 and n-6 PUFA on NAFLD. In regards to the effect of olive oil on inflammatory status, evidence from animal model, suggested that olive oil, significantly improves glucose homeostasis and inflammatory status through regulation of TNF-α IL-1, IL-10, and adipokines (58). On the other hand, olive oil also reduces the oxidative and nitrosative stress induced by a high fat diet in the liver and a high oxidation of liver fatty acids (58). Olive oil reduces NF-κB activation and improves insulin resistance (58). Another animal study by Zhang et al. showed that flaxseed oil significantly reduced liver inflammation by reducing plasma and liver tissue levels of TNF-α, IL-1β and IL-6 in alcoholic fatty liver disease (59). There is limited evidence that there appears to be a gap in the oxidation of unsaturated and saturated fats. However, irrespective of the discrepancy, some unsaturated fatty acids may stimulate general fat oxidation by activating transcription factors as Peroxisome proliferator-activated receptors (PPARα) (60). Animal studies and a limited number of early human clinical trials have suggested that PPARα has a protective effect on NASH through certain important mechanisms, such as inducing expression of genes involved in beta oxidation, decreasing inflammation, decreasing oxidative stress, and increasing the secretion of beneficial adipokines like adiponectin (61).

Effects of n-3 PUFA supplementation on liver histological parameters

In line with the previous systematic review and meta-analysis(13), there is no effect of n-3 PUFA supplementation on fibrosis score, hepatocellular ballooning score, lobular inflammation score, and NAS. Of the 5 studies that reported liver histology outcomes, 2 studies showed a significant improvement in liver histology outcomes with n-3 PUFA supplementation in combination with a hypocaloric or heart healthy diet for 24 weeks (22, 23). However, it was suggested that supplementation with n-3 PUFA may be beneficial at the early stage of NAFLD. The incorporation of a combination of dietary interventions can address the multiple impacts occurring during the onset and evolution of NAFLD (62).

Effects of n-3 LC-PUFA supplementation on liver fat content, steatosis score and enzymes

Liver fat

The inconclusive effects of n-3 PUFA supplementation on NAFLD liver fat content was consistent with the results of previous systematic review and meta-analysis(13). In the current systematic review, only one study found a significant reduction in liver fat content, assessed by MRI, with n-3 PUFA supplementation along with a hypocaloric diet for 52 weeks (21). In contrast, previous systematic reviews and meta-analyses reported a beneficial effect of n-3 PUFA supplementation on liver fat (12, 14). These studies also found an effect size favouring n-3 PUFA treatment. Although these meta-analyses used a random effect model due to significant heterogeneity among included studies (12, 14).

Steatosis score

The effects of n-3 PUFA supplementation on steatosis score assessed by ultrasonography and CT scan were similar to previous systematic reviews (12–14). In the present review, of the 5 studies, 3 studies indicated a significant reduction in steatosis scores with the n-3 PUFA supplementation (31, 37, 46). Two studies have used American Health Foundation diet and n-3 PUFA supplementation. However, the effects of dosage and duration of the intervention on the changes in the steatosis score were inconclusive because a higher dose (6 g/day), longer duration (12 months) and a lower dose (0.83 g/day), short duration (6 months) of n-3 PUFA supplementation produced similar results.

Liver enzymes

Contrary to previous systematic reviews and meta-analyses (12–14, 63), the effects of the n-3 PUFA intervention on ALT and AST levels were inconclusive in our current systematic review. Using n-3 PUFA supplementation 4 studies showed a significant reduction in ALT and AST levels (25, 26, 37, 45), 3 studies showed a significant decrease only in serum ALT levels (26, 37, 45), and only one study demonstrated a significant reduction in serum AST levels in intervention group(25). There were 2 studies that reported significant reduction in serum ALT and AST levels in the control group but not in the intervention group (29, 30). For control group, both studies used olive oil (29, 30). Additionally, there was also a significant reduction in ALT and AST with a macronutrient modified diet and n-3 PUFA supplementation(37, 46). These studies used the American Heart Foundation diet, which consisted of 50% carbohydrate, 20% protein and 30% fat (37, 46). Similarly, some studies that used dietary approaches, showed a significant reduction in serum ALT and AST levels (39, 40).

Although the majority of RCTs examined the effect of n-3 PUFA supplementation in combination of hypocaloric or hearth healthy diet on liver related outcomes. Only 35% of studies indicated that n-3 PUFA supplementation may attenuate liver enzyme levels and a small number of studies (20%) found a reduced steatosis score. As the duration of the intervention ranges from 6 weeks to 78 weeks, along with the wide range of n-3 PUFA doses. As a result, it is difficult to determine the optimal dose of n-3 PUFA supplementation for improvement of liver-related outcomes.

The present systematic review has several strengths. First, we selected primary outcomes of liver related outcomes i.e., liver histological outcomes, liver fat content, steatosis score and liver enzyme levels. Because it gave a more comprehensive indication of the effect of fatty acids on liver related outcomes. Second, a broad definition of the fatty acids was evaluated, which ranged from specific fatty acids, such as total fat, SFA, MUFA and PUFAs, fat modified diets and cooking oil. The inclusion of both dietary and supplemental fatty acid intake allowed for a relatively comprehensive review of the association with NAFLD. Third, the search strategy was extensive and comprehensive, using six electronic databases. Fourth, 31 RCTs and 5 case-control studies with large sample sizes and sample diversity across 16 countries were included, thus enabling a full evaluation of fatty acid intake on NAFLD in adult populations worldwide. Fifth, the quality assessment tools, ROB 2.0 for RCTs and the JBI checklist for case-control studies, allowed for risk of bias assessment at the study level using. Majority of RCTs (79%) and case-control studies (66%) had a low risk of bias. Finally, most studies in this systematic review investigated both male and female participants.

Of course, it also comes with its limitations, mainly the heterogeneity of the duration of interventions, a broad range of liver related outcome as well as outcome measures, and that pooled results from meta-analysis were not conducted. Additionally, the participant inclusion criteria included all adults with NAFLD, except those with any acute or chronic disease and that inherently affects dietary intake. Further, we excluded the lower quality case-control studies due to the non-report of information regarding confounding factors and strategies to deal with confounding factors. Also, given the inconsistencies of types of dietary and supplemental fat, dosages and the duration of intervention, the systematic review could not provide any recommendation related to optimal dosage and duration of fatty acid supplementation for the treatment of NAFLD. Finally, the heterogeneity of the studies (i.e., age, geographic location, study quality, severity of NAFLD, and adjustment for main confounders) prevented the synthesis of a meta-analysis.

This systematic review provides an update on the effect of dietary and supplemental fatty acid intake on NAFLD. Results from the current review revealed that dietary fatty acid composition plays an important role in liver related outcomes in NAFLD patients. Overall n-3 PUFA supplementation in combination with a hypocaloric or heart healthy diet may improve liver enzymes levels, however, further research is required to examine the effect of n-3 PUFA supplementation with a diet rich in healthy fat and low SFA. The use of cooking oils such as flax or olive oil or canola oil or a combination of three oils can be beneficial for the reduction of liver fat content. Existing evidence of the mechanism of dietary fatty acid composition or ratio on NAFLD is limited. Additionally, effect of individual fatty acid on NAFLD is limited because it is difficult to isolate certain fatty acids from foods. More studies with large samples, an adequate methodological design is recommended to understand the mechanism of specific fatty acids to modify hepatic outcomes in patients with NAFLD.

Declarations

Contributions

AD contributed to conceptualisation, methodology, executed the search, screening, quality assessment, data extraction, data synthesis, writing of original draft, review and editing the manuscript. AD and YT contributed to screening, quality assessment and data extraction. All co-authors reviewed and provided critical feedback on the manuscript. All authors approved the final manuscript.

Conflict of interests:

The authors have no relevant interests to declare.

Funding

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Fatty acid composition but not quantity is an important indicator of Non-alcoholic Fatty Liver Disease: A Systematic Review

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Abstract

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Introduction

Method

Search strategy

Screening and selection criteria

Data extraction

Quality Assessment

Results

Study selection

Quality assessment

Characteristics of included studies

Outcomes

Effects of dietary fat and fatty acids on NAFLD

Case control studies

Effects of dietary fat on histologic parameters and liver fat content

RCTs

Effects of dietary fat on liver enzymes

Effects of n-3PUFA supplementation on histologic parameters

Effects of n-3 PUFA supplementation on liver fat content

Effects of n-3 PUFA supplementation on steatosis score assessed by ultrasonography

Effects of n-3 PUFA supplementation on liver enzymes

Discusssion

Effects of total dietary fat and fatty acids on NAFLD

Effects of n-3 PUFA supplementation on liver histological parameters

Effects of n-3 LC-PUFA supplementation on liver fat content, steatosis score and enzymes

Liver fat

Steatosis score

Liver enzymes

Conclusion

Declarations

Declarations

Funding

References

Additional Declarations

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