Impact of a Mediterranean Diet on Hepatic and Metabolic Outcomes in Non-alcoholic Fatty Liver Disease

The Medina Randomised Controlled Trial

Elena S. George; Anjana Reddy; Amanda J. Nicoll; Marno C. Ryan; Catherine Itsiopoulos; Gavin Abbott; Nathan A. Johnson; Siddharth Sood; Stuart K. Roberts; Audrey C. Tierney


Liver International. 2022;42(6):1308-1322. 

In This Article

Abstract and Introduction


Background: Non-alcoholic fatty liver disease (NAFLD) is predominantly managed by lifestyle intervention, in the absence of effective pharmacotherapies. Mediterranean diet (MedDiet) is the recommended diet, albeit with limited evidence.

Aims: To compare an ad libitum MedDiet to low-fat diet (LFD) in patients with NAFLD for reducing intrahepatic lipids (IHL) by proton magnetic resonance spectroscopy (1H-MRS). Secondary outcomes include insulin resistance by homeostatic model of assessment (HOMA-IR), visceral fat by bioelectrical impedance analysis (BIA), liver stiffness measurement (LSM) and other metabolic outcomes.

Methods: In this parallel multicentre RCT, subjects were randomised (1:1) to MedDiet or LFD for 12 weeks.

Results: Forty-two participants (25 females [60%], mean age 52.3 ± 12.6 years) were included, 23 randomised to LFD and 19 to MedDiet.; 39 completed the study. Following 12 weeks, there were no between-group differences. IHL improved significantly within the LFD group (−17% [log scale]; p = .02) but not within the MedDiet group (−8%, p = .069). HOMA-IR reduced in the LFD group (6.5 ± 5.6 to 5.5 ± 5.5, p < .01) but not in the MedDiet group (4.4 ± 3.2 to 3.9 ± 2.3, p = .07). No differences were found for LSM (MedDiet 7.8 ± 4.0 to 7.6 ± 5.2, p = .429; LFD 11.8 ± 14.3 to 10.8 ± 10.2 p = .99). Visceral fat reduced significantly in both groups; LFD (−76% [log scale], p = <.0005), MedDiet (−61%, p = <.0005).

Conclusions: There were no between-group differences for hepatic and metabolic outcomes when comparing MedDiet to LFD. LFD improved IHL and insulin resistance. Significant improvements in visceral fat were seen within both groups. This study highlights provision of dietary interventions in free-living adults with NAFLD is challenging.


Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide, affecting approximately 20%–30% of the adult population.[1] NAFLD results from an accumulation of fat in the liver which exceeds 5% of total liver weight and occurs in the absence of excessive alcohol consumption.[2] NAFLD is often referred to as the hepatic manifestation of metabolic syndrome as it tends to occur with one or more risk factors that define the syndrome including insulin resistance, hypertension, obesity and/or hyperlipidaemia.[3,4] A variety of therapeutic interventions have been proposed for the management of NAFLD; these have predominantly focused on weight reduction using low-calorie diets, exercise, pharmacotherapy or bariatric surgery, as well as lipid-lowering drugs and antioxidant supplementation.[5] In the absence of effective and safe pharmacotherapy, diet and lifestyle interventions remain the first-line treatment in NAFLD. The most effective treatment to date is weight loss and there seems to be a direct relationship between percentage weight loss and improvement in risk factors.[6–8] In real-world settings, weight loss continues to be difficult to achieve and even harder to maintain, with long term follow-up studies confirming that weight loss is generally not sustained.[9,10]

A large body of literature surrounds the benefits of a Mediterranean diet (MedDiet) in conditions such as metabolic syndrome, T2DM and cardiovascular disease; such conditions often co-exist and have a pathophysiological link with NAFLD.[11,12] A small but growing body of evidence from randomised controlled trials (RCTs) continues to demonstrate that increased adherence to a MedDiet, in patients with NAFLD can improve intrahepatic lipid (IHL) levels, fibrosis, insulin resistance and other metabolic risk markers.[13–17] These trials are heterogeneous with varying clinical outcomes, including relatively few with hepatic specific measures. In addition, prescribed dietary interventions within the studies are variable and thus there is lack of consistent high-quality evidence to support a superior dietary pattern for this patient group.

Mediterranean diet interventions are also largely limited to Mediterranean regions and thus the feasibility and efficacy of achieving dietary adherence in patients with NAFLD from Western, multiethnic populations have not been determined.[18–20] One tightly controlled trial conducted in Australia, which included the full provision of meals, demonstrated adherence to MedDiet-elicited reversal of NAFLD through reducing IHL (−39%) and improving insulin resistance (−1.7 mmol/L, using HOMA-IR) in 6 weeks.[14] Another RCT in free-living adults with NAFLD in Australia found MedDiet and a low-fat diet (LFD) both effectively improved hepatic steatosis indicating that improved diet quality regardless of dietary prescription was beneficial.[15] Still, current dietary guidelines for patients with NAFLD encompass the principles of an LFD, which underpin the National Dietary Guidelines.[21,22] There is limited evidence supporting the efficacy of LFD for the improvement of hepatic and cardio-metabolic risk factors in NAFLD. Benefits that have been reported following the provision of LFD are elicited because of the effects of weight loss and not necessarily the effects of the diet itself.[23,24]

Therefore, the aims of this RCT were to compare an ad libitum MedDiet to a LFD in patients with NAFLD by comparing the efficacy of the two dietary patterns in relation to several metabolic parameters including primary outcome IHL, and secondary outcomes, including insulin resistance as determined by homeostatic model of assessment of insulin resistance (HOMA-IR). In addition, we assessed whether there are health benefits attributed to adhering to these dietary guidelines and prescriptions in the absence of weight loss.