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. 2019 Mar 21;11(3):677. doi: 10.3390/nu11030677

Table 3.

The published systematic reviews, meta-analysis, human clinical trials and cross-sectional analysis using a liver biopsy to evaluate the effect of macronutrient composition in NAFLD.

SATURATED FATS
Author, Year Study Design n Intervention Time of Intervention Results
Mozaffarian et al., 2010 [22] A Systematic Review and Meta-Analysis of 8 randomized controlled trials 13,614 participants Evaluate studies with increased PUFA consumption as a replacement for SFA and report the incidence of myocardial infarction and/or cardiac death 1–8 years Consuming PUFAs in place of SFA reduces the occurrence of coronary heart disease events by 19%, corresponding to a 10% reduced coronary heart disease risk (RR = 0.90, 95% CI = 0.83–0.97) for every 5% energy increase of PUFAs
MONOUNSATURATED FATS
Schwingshackl et al., 2011 [26] A Systematic Review and Meta-Analysis of 9 randomized controlled intervention trials 1547 patients with an abnormal glucose metabolism and being overweight or obese Evaluate the effects of diets high in MUFAs vs. diets low in MUFAs in glycemic control of T2D 6–48 months An improvement in Hb1Ac (weighted mean difference–0.21%, 95% CI −0.40 to −0.02; p = 0.03) was evidenced but without improvement in fasting plasma glucose or HOMA-IR. MUFAs consumption should be recommended in T2D
POLYUNSATURATED OMEGA-3 FATS
Toshimitsu et al., 2007 [38] Applied nutritional investigation 46 patients (28 with biopsy-proven NASH vs. 18 with simple steatosis) Dietary habits and nutrients intake were analyzed through detailed questioning by physicians and dieticians 3 consecutive days A higher intake of simple carbohydrates and lower intake of protein, PUFAs and zinc
Hartweg et al., 2009 [34] A Systematic Review of 23 randomized controlled intervention trials 1075 T2D patients with cardiovascular risk factors Effect of omega-3 PUFAs supplementation on NAFLD (mean dose: 3.5 g/day; mean treatment duration: 8.9 weeks) 4 weeks–8 months Improved triglyceride (lowered by 0.45 mmol/L (95% CI −0.58 to 0.32, p < 0.00001)) and VLDL cholesterol (lowered by −0.07 mmol/L (95% CI −0.13 to 0.00, p = 0.04)). May raise LDL cholesterol (non-significant in subgroups). No statistically significant effect on body weight, glycemic control, fasting insulin, total or HDL-cholesterol
Parker et al., 2012 [41] A Systematic Review and Meta-Analysis of 9 randomized controlled intervention trials 355 patients given either omega-3 PUFAs or the control treatment were included Effect of omega-3 PUFAs supplementation on NAFLD (median dose: 4 g/day (range: 0.8–13.7 g/day); median treatment duration: 6 months) 8 weeks–12 months Improvement in liver fat (−0.97, 95% CI −0.58 to −1.35, p < 0.001) and in AST levels (−0.97, 95% CI −0.13 to −1.82, p = 0.02), however, substantial heterogeneity was found and an optimal dose was not clarified
Sanyal et al., 2014 [44] Phase 2b multicenter, double-blinded, randomized, placebo-controlled trial 243 patients with NASH and NAFLD activity scores >4 (75 receives placebo, 82 low-dosage EA (1800 mg/d), 86 high-dosage EA (2700 mg/d)). Liver biopsies were collected 2 weeks after the last dose. The primary efficacy endpoint was NAS <3, without worsening of fibrosis; or a decrease in NAS by >2 without the worsening of fibrosis 12 months No significant histological effects or blood markers improvement. However, with 2.7 g of EA, reduced levels of triglyceride were observed (−6.5 mg/dL vs. an increase of 12 mg/dL in the placebo group; p = 0.03)
Nogueira et al., 2016 [46] Randomized controlled trial 50 patients with biopsy-proven NASH (23 received placebo (mineral oil), 27 received omega-3 PUFAs (flaxseed oil and fish oil)). Liver biopsies, plasma biochemical markers of lipid metabolism, inflammation, liver function and plasma levels of omega-3 PUFAs were assessed as a marker of intake at the baseline and after 6 months of treatment 6 months No histological improvement was seen after a six-month use of flaxseed oil and fish oil despite ALA, EA and triglycerides levels significantly improved. NAS improvement was correlated with increased PUFAs plasma levels
FRUCTOSE
Abdelmalek et al., 2010 [66] Cross-sectional study 427 NAFLD patients Block food questionnaire data were collected within 3 months of a liver biopsy 3 months Daily fructose ingestion from fruit juice and soft drinks is associated with lower steatosis grade and higher fibrosis stage. In patients >48 years, an association with hepatic inflammation and ballooning was found (p < 0.05)
DIETARY FIBER
Daubioul et al., 2005 [78] Randomized, double-blinded, crossover study 7 patients with biopsy-proven NASH Daily ingestion of 16 g of oligofructose or maltodextrin (placebo) 8 weeks Daily oligofructose ingestion decreases serum aminotransferases and improves insulin levels
PROBIOTICS
Malaguarnera et al., 2011 [86] Randomized controlled trial 66 patients with biopsy-proven NASH (33 patients received Bifidobacterium longum with fructooligosaccharides and lifestyle modification vs. 33 with lifestyle modification alone) Analytic assessment at 0, 6, 12, 18, and 24 weeks. Liver biopsies were performed at entry and repeated after 24 weeks of treatment 24 weeks Bifidobacterium longum with fructooligosaccharides and lifestyle modification when compared to lifestyle modification alone, significantly reduces TNF-α, CRP, serum AST levels, HOMA-IR, serum endotoxin, steatosis, and the NASH activity index (p ≤ 0.05)
Maet al.,2013 [73] Meta-Analysis of 4 randomized controlled trials 134 patients Assess the efficacy of probiotic therapies in modifying liver function, fat metabolism and insulin resistance 8 weeks–6 months Probiotics can reduce insulin resistance, liver aminotransferases, total-cholesterol and TNF-α. However, the use of probiotics was not associated with changes in BMI, glucose and LDL-cholesterol
Loman et al., 2018 [89] Systematic Review and Meta-Analysis of 25 randomized controlled trials 1309 patients with NAFLD Systemically review and quantitatively synthesize evidence on prebiotic, probiotic, and synbiotic therapies for NAFLD 1.5–4.3 months Reduction in BMI (0.37 kg/m2; 95%CI: 0.46 to 0.28; p < 0.001), liver enzymes (ALT, 6.9 U/L (95%CI: 9.4 to 4.3); AST, 4.6 U/L (95%CI: 6.6 to 2.7); GGT, 7.9 U/L (95%CI: 11.4 to 4.4); p < 0.001), serum cholesterol (10.1 mg/dL 95%CI: 13.6 to 6.6; p < 0.001), serum cholesterol LDL-c (4.5 mg/dL; 95%CI: 8.9 to 0.17; p < 0.001) and triglycerides (10.1 mg/dL; 95%CI: 18.0 to 2.3; p < 0.001), however, no changes in inflammation (TNF-α and CRP) were reported
COFFEE
Saab et al., 2014 [92] Systematic review of case-control or cross-sectional studies 2723 NAFLD patients Effects of coffee on liver diseases - Coffee consumption was associated with improved serum GGT, AST and ALT values in a dose-dependent manner. Coffee consumption was inversely correlated to NASH severity
ALCOHOL
Dunn et al., 2012 [98] Cross-sectional Analysis 582 biopsy-proven NAFLD patients (251 lifetime non-drinkers vs. 331 modest drinkers (≤2 drinks/day)) Evaluate the association between modest alcohol drinking (lifetime drinking history questionnaire) and NASH among subjects with biopsy-proven NAFLD - Modest drinkers had lower odds of having a diagnosis of NASH (summary OR 0.56, 95%CI: 0.39–0.84, p = 0.002), fibrosis (OR 0.56 95%CI: 0.41–0.77) or ballooning (OR 0.66 95%CI 0.48–0.92)
Kwon et al., 2013 [99] Cross-sectional Analysis 77 biopsy-proven NAFLD patients Determine alcohol consumption effect (lifetime alcohol consumption questionnaire) on NAFLD histological severity - Some degree of regular alcohol consumption (≥24 gram-years) vs. minimal intake appears to have a protective effect on NAFLD histological severity (OR 0.26, 95%CI: 0.07–0.97, p = 0.04)

PUFAs: polyunsaturated fats; SFA: saturated fats; RR: risk ratio; MUFAs: monounsaturated fats; T2D: type 2 diabetes; HOMA-IR: homeostatic model assessment of insulin resistance; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; AST: aspartate aminotransferase; NAS: NAFLD activity score; EA: eicosapentaenoic acid; ALA: alpha-linolenic; TNF-α: alpha tumor necrosis factor; CRP: C reactive protein; BMI: body mass index; ALT: alanine aminotransferase; GGT: gamma-glutamyl transferase; OR: odds ratio.