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.