Mediterranean diet and nonalcoholic fatty liver disease

Table 1 Traditional Mediterranean diet components

Components	Consumption	Rich in
Fresh fruits	Daily, 3 servings	Vitamin C, polyphenols, carotenoids, fibers
Vegetables	Daily, 6 servings	Vitamin C, polyphenols, ω-3-PUFA, carotenoids, fibers
Olive oil	Daily1	MUFA, polyphenols
Unrefined cereals	Daily, 8 servings	Polyphenols, fibers
Nuts	Weekly	Polyphenols, ω-3-PUFA, fibers
Legumes	Weekly, ≥ 3 servings	Polyphenols, fibers
Fish	Weekly, 5-6 servings	ω-3-PUFA
Red wine	Weekly, ≥ 7 glasses	Polyphenols

¹As the main added lipid.

Table 2 Cross sectional studies on the association between Mediterranean diet and non-alcoholic fatty liver disease

Authors, year, country[ref.]	Patient population	NAFLD Diagnosis	Adherence to MD	Comment
Kontogianni, 2014, Greece[34]	73 overweight/obese adult patients with NAFLD vs 58 age-, gender-, and BMI-matched controls with normal liver ultrasound/liver chemistry	Patients who met all the following criteria: abnormal ALT and/or GGT; ultrasound evidence of hepatic steatosis and/or compatible liver histology; and no other cause of liver steatosis	Adherence to MD (as estimated by MedDietScore) did not differ significantly between patients and controls	Higher adherence to MD was not associated with lower likelihood of having NAFLD (even after adjustment with abdominal fat level). However, it was associated with lesser degree of insulin resistance and less severe liver disease among patients with NAFLD
Aller, 2015, Spain[35]	82 adult patients with NAFLD (of whom 56 had NASH, and 26 non-NASH; 35 had steatosis grade 1, and 47 steatosis grades 2 and 3)	Liver biopsy in all 82 patients	Higher adherence to MD (as estimated by the 14-item MD assessment tool) was higher in patients with low grade of steatosis than in those with high grade, in patients without NASH than in those with NASH, and in patients without liver fibrosis than in those with liver fibrosis	In the logistic regression analysis,one unit of the 14-item MD assessment tool was associated with a lower likelihood of having NASH (OR = 0.43) and steatosis (OR = 0.42)
Chan, 2015, Hong Kong[36]	797 apparently healthy Chinese adults (332 male, 465 female) of whom 220 (27.6%) had diagnosis of fatty liver	1H MRS was performed to measure IHTG. Fatty liver was defined as IHTG ≥ 5%	Subjects with fatty liver showed lower gender-adjusted MD score than those without fatty liver	Multivariate adjusted regression analyses showed an inverse association between MD score and prevalence of fatty liver, which approached the level of significance
Trovato, 2016, Italy[37]	1199 overweight/ obese adult patients with (n = 532) and without (n = 667) hepatic steatosis	Hepatic steatosis and its severity were assessed by ultrasound	Greater prevalence of overweight/ obesity (as assessed by BMI) and insulin resistance (as assessed by HOMA-IR), sedentary life habits, increased TG and HDL-C, greater use of Western diet food, as well as poor adherence to MD (as assessed by 1-wk recall questionnaire) were found in patients with hepatic steatosis vs those without it	Multiple regression analysis, weighted by years of age, displayed BMI, HOMA-IR and adherence to MD as the most powerful predictors of hepatic steatosis severity
Baratta, 2017, Italy[38]	584 overweight/obese adult patients with ≥ 1 CVD risk factor	Ultrasound evaluation	57 (9.8%) patients had low MD adherence (as estimated by Med-Diet questionnaire), while 436 (74.6%) and 91(15.6%) had, respectively, intermediate and high MD adherence. NAFLD prevalence significantly decreased from subjects with low to high adherence to MD (from 96.5% to 71.4%, P < 0.001)	In a multiple logistic regression analysis, MD adherence (intermediate vs low OR = 0.115; P = 0.041; high vs low OR: 0.093; P = 0.030) were independently associated with NAFLD
Cakir, 2016, Turkey[39]	Overweight/obese children with (n = 106, Group 1) and without (n = 21, Group 2) hepatic steatosis; and children with normal BMI and without known chronic disease (n = 54, Group 3)	Assessment of hepatic steatosis and its severity by ultrasound	Prevalence of a low level of MD adherence (as established by KIDMED index score) was significantly higher in Group 1 children compared to those belonging to Groups 2 or 3	The level of adherence to MD was negatively correlated with BMI, but no significant correlation was found with ALT, total body fat, TG, and HOMA-IR. No significant difference in the level of MD adherence was found between patients with hepatic steatosis grade1 and those with grades 2 and 3
Della Corte, 2017, Italy[40]	4 subgroups of overweight/obese children: with and without fatty liver; with and without NASH.	Among the 243 study children, ultrasound identified and excluded fatty liver in 66 and 77, respectively. The remaining 100 underwent liver biopsy identifying and excluding NASH in 53 and 47, respectively	Prevalence of a low level of adherence to MD (as estimated by KIDMED score) was significantly higher in patients with NASH compared to those without NASH as well as to those with and without fatty liver (100% vs 28.8% vs 37.9% vs 9.1%; P = 0.01)	Poor adherence to MD was associated to severe liver damage, with a negative correlation with NAFLD activity score and fibrotic stage

ALT: Alanine aminotransferase; BMI: Body mass index; CVD: Cardiovascular disease; GGT: Gamma-glutamyl transferase;

¹H MRS: Proton magnetic resonance spectroscopy; HOMA-IR: Homeostasis model assessment of insulin resistance; IHTG: Intrahepatic triglyceride content; MD: Mediterranean diet; NAFLD: Non-Alcoholic Fatty Liver; NASH: Non-Alcoholic Steatohepatitis; OR: Odds ratio; TG: Triglycerides.

Table 3 Longitudinal studies on the effects of Mediterranean diet on non-alcoholic fatty liver disease in adult patients

Authors, year, country[ref.]	Study design	Patient population	Intervention (duration, type, number of patients)	Liver outcome	Other outcomes
Fraser, 2008, Israel[41]	An open label, parallel design, quasi-randomized (allocation by alternation) controlled trial	Overweight /obese patients with T2DM	3 groups at 6/12 mo: 1. ADA diet, n = 64/54; 2. Low GI diet, n = 73/64; 3. Modified MD, n = 64/61. Energy contents similar in all three diets	ALT levels significantly decreased at 6 and 12 mo in modified MD vs low GI or ADA diets, independently of waist to hip ratio, BMI, HOMA and triacylglycerol values
Bozzetto, 2012, Italy[43]	Randomized, controlled, parallel-group design	36 overweight /obese patients with T2DM	8 wk, 4 groups: 1. High-CHO/ high-fiber/ low GI diet, n = 9; 2. MUFA diet, n = 8; 3. High-CHO/ high-fiber/ low GI diet + exercise, n = 10; 4. MUFA diet + exercise, n = 9.	Liver fat (as measured by 1H MRS) decreased more in groups 2 (-25%) and 4 (-29%) than in groups 1 (-4%) or 3 (-6%). Two-way repeated-measures ANOVA showed a significant effect on liver fat content for MUFA diet, independently of exercise. There were no significant ALT and AST changes in all groups.	At the end of intervention, there were no significant changes in body weight,WC, as well as in glucose, total cholesterol, LDL-C, HDL-C, TG, and HOMA-IR values from baseline in all groups
Ryan, 2013, Australia[42]	A randomized, controlled, cross-over study	12 non-diabetic patients with a biopsy-proven NAFLD at baseline	A cross-over 6-wk dietary intervention study comparing traditional MD vs low fat/high-CHO	MD group demonstrated a significant decrease in liver fat (as measured by 1H MRS) compared to the low fat/ high-CHO group (39% vs 7%). ALT and GGT did not significantly decrease with either diet	At the end of intervention, no significant changes in body weight, WC, as well as in TG, and HDL-C in both groups. Peripheral insulin sensitivity improved only in the MD group. Systolic BP declined significantly in both groups, though to a lesser degree in the low fat/ high-CHO group
Trovato, 2015, Italy[44]	Single arm	Non-diabetic overweight/obese patients with ultrasound evaluation of liver fat changes from baseline	90 patients following intervention with MD alone for 1, 3, and 6 mo	Liver fat significantly decreased only after 6 mo of intervention. By a multiple linear regression model, changes in adherence to the MD and BMI were found to independently explain the variance of decrease of liver fat (R2 = 0.519; P < 0.0001). No significant ALT changes were observed throughout the follow-up	Significant decrease of BMI followed by parallel increases of the MD adherence as well as of physical activity were observed from the first month of intervention. Significant decrease of HOMA-IR was observed only after 3 and 6 mo
Abenavoli, 2015, Italy[45]	Controlled randomized study	Overweight/obese patients with ultrasound evaluation of liver fat changes from baseline	6 mo, 3 groups: 1. Hypocaloric MD, n = 10; 2. Hypocaloric MD plus Realsil complex, n = 10; 3. No treatment, n = 10.	Compared to the group that did not undergo any treatment, MD either alone or associated with the Realsil complex led to significant improvement in liver steatosis	Compared to the group that did not undergo any treatment, those following the MD either alone or associated with the Realsil complex had improvement in BMI, WC, hip circumference, as well as in total cholesterol, and TG. Improvement in insulin sensitivity occurred only in patients receiving MD plus the Reasil complex
Misciagna, 2016, Italy[46]	Randomized, controlled, parallel-group design	A population almost composed of non-diabetic overweight/ obese patients (18 to 79 years old, without overt CVD) with ultrasound evaluation of liver fat at baseline and follow-up	3 and 6 mo, 2 groups: 1. MD with low GI, n = 44; 2. Control diet(based on INRAN guidelines), n = 46	MD with low GI was associated until 55 yr of age, in both men and women, with a more intense reduction in liver fat than a control diet, at both the 3rd and 6th month	Six months after intervention, in both groups, the number of obese patients decreased while the number of overweight subjects increased. Lower TG and glucosemia were found at 6 mo in both groups
Gelli, 2017, Italy[33]	Single arm	46 (11 normal weight; 35 overweight/obese) subjects (42 with ≥ 1 MetS component; 4 with T2DM) with ultrasound evaluation of liver fat at baseline and follow-up	All patients followed intervention with MD alone for 6 mo	At end-intervention, the percentage of patients with hepatic steatosis grade ≥ 2 was reduced from 93% to 48%; mean AST, ALT, GGT decreased significantly	At end of intervention, of the 35 overweight/obese patients, 12 showed ≥ 7% weight reduction while 7 achieved normal weight; mean serum total cholesterol, HDL-C, AST, TG, glucose concentrations, and HOMA-IR values significantly improved

ADA: American Diabetes association; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BMI: Body mass index; BP: Blood pressure; CHO: Carbohydrates; GGT: Gamma-glutamyl transferase; GI: Glycemic index;

¹H MRS: Proton magnetic resonance spectroscopy; HDL-C: High density lipoprotein-cholesterol; HOMA-IR: Homeostasis model assessment of insulin resistance; INRAN: Italian National Research Institute for Foods and Nutrition; LDL-C: Low density lipoprotein-cholesterol; MD: Mediterranean diet; MetS: Metabolic syndrome; MUFA: Monounsaturated fatty acid; T2DM: Type 2 diabetes mellitus; TG: Triglycerides; WC: Waist circumference.