Ad Libitum Mediterranean or Low‐Fat Diets as Treatments for Nonalcoholic Fatty Liver Disease?
Authors: Giovanni Targher, Christopher D. Byrne
Journal: Hepatology (2018)

See Article on page 1741 The 2016 European Society of Cardiology guidelines recommended a total fat intake of ≤30%, of which ≤10% should consist of saturated fats to reduce risk of cardiovascular disease (CVD).1 These guidelines also suggested decreasing saturated fat intake by substitution with polyunsaturated fatty acids.1 In June 2017, the American Heart Association's presidential advisory on dietary fats stated that replacing saturated fat with polyunsaturated vegetable oil reduces the incidence of CVD by ~30%.2 Importantly, this shift from saturated to unsaturated fats occurs when a Westernized diet containing processed foods is replaced by the Mediterranean diet (MD).2 Traditionally, the MD contains an abundance of plant foods, including legumes, vegetables, fruits, nuts, grains, and fish.3 Several observational cohort studies and some randomized clinical trials (RCTs) have suggested that the MD reduces the incidence of CVD.3 Currently, there are no licensed pharmacological agents for the treatment of nonalcoholic fatty liver disease (NAFLD). Lifestyle changes, including hypocaloric diet and increases in physical activity, are and should be the first line of treatment in NAFLD.4 Weight loss is beneficial in NAFLD, and Vilar et al. reported a dose‐response relationship between percentage weight loss and histological changes in nonalcoholic steatohepatitis (NASH), with the greatest reduction among individuals with the most weight loss.5 Accordingly, the 2016 European Association for the Study of the Liver (EASL)/European Association for the Study of Diabetes (EASD)/European Association for the Study of Obesity (EASO) Clinical Practice Guidelines6 recommended that in overweight/obese patients with NAFLD, a 7%‐10% weight loss is the goal of most lifestyle interventions and results in improvements of both serum liver enzymes and liver histology. Considering the current evidence, recommending the MD for patients with NAFLD might be an appropriate therapeutic option,7 not least because patients with NAFLD are at increased risk of CVD.6 However, the evidence that the MD is beneficial in NAFLD is based on a few observational studies and small, short‐term RCTs.7 Currently, the MD is also recommended by the EASL–EASD–EASO Clinical Practice Guidelines for NAFLD (Grade, B1).6 The MD is particularly attractive in NAFLD given that it may benefit the liver, independently of concomitant weight loss.4 Data from two small, short‐term RCTs have suggested a potential beneficial effect of the MD on NAFLD.8 In a randomized, parallel‐group design trial,8 45 patients with type 2 diabetes were assigned to two 8‐week isocaloric diets: either a high‐carbohydrate/‐fiber diet or a high‐monounsaturated fatty acid (MUFA) diet. Liver fat content, measured by magnetic resonance spectroscopy (MRS), decreased more in the MUFA group (−29%) than in the high‐carbohydrate/‐fiber group (−4%), despite no weight loss in both groups. In the other randomized, crossover 6‐week trial enrolling 12 nondiabetic subjects with NAFLD, who were assigned to two isocaloric diets (MD vs. standard low‐fat/high‐carbohydrate diet),9 there was a significant relative reduction in hepatic steatosis (HS) after the MD compared to the low‐fat/high‐carbohydrate diet (–39% vs. –7% as measured by MRS), despite modest weight loss that was not different between the two diets. The findings of Properzi et al.10 add additional information to the body of evidence supporting dietary changes in NAFLD. The researchers show that ad libitum isocaloric MD and low‐fat diets (LFDs) are equally effective in reducing liver fat content (measured by MRS) in NAFLD. In a randomized, parallel‐group design trial of 51 middle‐aged obese (mean body mass index, 31 kg/m2) individuals with NAFLD, who were randomly assigned to a 12‐week single‐blinded dietary intervention (MD or LFD; with a daily energy intake of nearly 2,400‐2,600 kCal for both diets during the trial), the researchers showed that HS decreased significantly in both groups, and there was no significant difference in the mean percentage reductions in liver fat content following the MD compared to the LFD (–32.4% vs. –25%). Similarly, there was no difference in NAFLD resolution following adjustment for baseline hepatic fat content between the two groups. Weight loss was minimal (nearly 1.5‐2.0 kg) and not different between the two groups, although there was a small reduction in waist circumference (~3‐ and ~4‐cm decrease) and an increase in physical activity energy expenditure (~14 metabolic equivalent of task [MET]‐h/week and ~15 MET‐h/week increase) for the low‐fat and MD diets, respectively. Notably, diet adherence was higher with the MD than with the LFD (88% vs. 64%); and among the secondary outcomes, the researchers found that the Framingham Risk Score, plasma lipids, and hemoglobin A1c improved significantly from baseline in the MD group only. No significant differences were observed between, or within groups, in markers of insulin resistance, and measures of both arterial stiffness and liver stiffness (as assessed by FibroScan).10 Collectively, although some of the observed benefits on liver fat content may have been attributed to a small decrease in abdominal adiposity (visceral fat mass) and an increase in physical activity energy expenditure, we consider that these findings are clinically relevant for patients with NAFLD and provide support for the view that both MD and LFD have the potential to improve HS (by approximately –25% to –30%), even in the absence of significant weight reduction.10 There are some differences in the benefits conferred by the MD versus the LFD on cardiometabolic risk factors, as illustrated in the linked article.10 Furthermore, the dietary components (or the absence of some dietary factors) that contribute to the benefit of either diet in NAFLD remain unclear. Nevertheless, in Fig. 1, we have suggested some of the dietary factors (or the absence of factors) that could mediate the beneficial effects of the MD and LFD on NAFLD and associated cardiometabolic risk factors. We have also speculated on how these two diets might favorably influence certain pathways involving the intestine, adipose tissue, and liver, to mediate benefits in NAFLD.Figure 1: Putative mechanisms by which ad libitum Mediterranean or low‐fat diets (and their individual dietary components) might contribute to the improvement of liver fat content and associated cardiometabolic risk factors in NAFLD. Abbreviations: BCAA, branched‐chain amino acids; DAGs, di‐acyl glycerol; di‐P‐PA, di‐palmitoyl phosphatidic acid; HDL‐cholesterol, high‐density lipoprotein‐cholesterol; LCFA, long‐chain fatty acids, LDL‐cholesterol, low‐density lipoprotein‐cholesterol; TAGs, tri‐acyl glycerols.Despite these promising results, we believe that longer‐term RCTs are needed, preferably with histological liver outcomes to test whether there is any benefit on NASH and/or hepatic fibrosis. It has to be stressed that, in most cases, any form of healthy diet (e.g., LFD or MD), which leads to caloric reduction and is acceptable to the patient, should be encouraged for patients with NAFLD. For the patient who finds caloric restriction difficult, changing dietary composition without necessarily reducing caloric intake could offer a more feasible alternative, although the benefit on liver health is not as marked as weight reduction alone.4 The importance of weight loss has been highlighted in patients with biopsy‐proven NASH, where weight loss per se is able to induce NASH resolution, without any worsening of fibrosis.5 If the MD is also effective in causing resolution of NASH, a weight‐reduction–centered approach ("weight‐normative") could be replaced in some patients with a healthy‐behaviors–centered approach ("weight‐inclusive"). That said, the evidence from this and other RCTs strongly supports the role of dietary changes as a primary therapy in NAFLD treatment. The question is no longer, is dietary change an effective therapy; rather, how can we ensure patient adherence to beneficial changes in their diet in NAFLD. Potential conflict of interest Nothing to report.