Wednesday, September 6, 2017

Mediterranean Diet and Antioxidant Formulation in Non-Alcoholic Fatty Liver Disease: A Randomized Study

Effect of Mediterranean Diet and Antioxidant Formulation in Non-Alcoholic Fatty Liver Disease: A Randomized Study
Ludovico Abenavoli 1,*, Marta Greco 1, Natasa Milic 2, Francesca Accattato 1, Daniela Foti 1, Elio Gulletta 1 and Francesco Luzza 1 1 Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy 2 Department of Pharmacy, University of Novi Sad, 21000 Novi Sad, Serbia * Received: 3 July 2017 / Accepted: 8 August 2017 / Published: 12 August 2017

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, characterized by liver fatty acid accumulation and fibrosis, not due to excessive alcohol consumption. Notably, nutritional habits have been reported to be implicated in the onset and severity of the hepatic damage, while the Mediterranean diet has shown beneficial effects on NAFLD. Free radicals and oxidative stress were suggested to be involved in the pathogenesis and progression of NAFLD, and several data highlighted the efficacy of antioxidant supplementation in its treatment. The aim of this study was to compare the effects of the Mediterranean diet, with or without an antioxidant complex supplement, in overweight patients suffering from NAFLD. In this prospective study, fifty Caucasian overweight patients were randomized into three groups (Groups A–C). A personalized moderately hypocaloric Mediterranean diet was prescribed to all patients included in the A and B groups. In addition to the diet, Group B was administered antioxidant supplementation daily and for the period of six months. Group C did not have any type of treatment. The study proved that the Mediterranean diet alone or in association with the antioxidant complex improved anthropometric parameters, lipid profile and reduced hepatic fat accumulation and liver stiffness. However, Group B patients, in which the diet was associated with antioxidant intake, showed not only a significant improvement in insulin sensitivity, but also a more consistent reduction of anthropometric parameters when compared with Group A patients. Taken together, these results support the benefit of antioxidant supplementation in overweight patients with NAFLD.

Discussion Only
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Despite the rapidly growing recognition of NAFLD over the last few decades, the treatment of this condition remains debated [39,40]. In the clinical management of NAFLD patients, a dietary change and increased physical exercise are essential to reduce body weight, in order to improve metabolic parameters and normalize the biochemical blood profile, as well as transaminase levels [24]. The “ideal” treatment for NAFLD should reduce the liver damage and its progression by reducing anthropometric parameters, by improving insulin resistance and impairment in glucose and lipid metabolism and by reducing the cytokine-mediated pathophysiological link between adipose tissue and liver [41]. The traditional Mediterranean diet is a dietary pattern that was associated with favorable health impact, in particular on cardiovascular diseases, cancer and in the treatment of metabolic syndromes [42]. Carotenoids, fibers and folic acid, which are basic components of this diet, can play a pivotal role in preventing or slowing down the oxidative stress process. In addition, vegetables, which are the staple foods included in the Mediterranean diet, are the main source of phytosterols, known as natural cholesterol-lowering agents, reducing cardiovascular risk [43,44].
Several pharmaceutical agents are currently being evaluated for the treatment of NAFLD, and NASH in particular. However, no single therapy has been approved so far [23,45]. On this basis, the beneficial effects of complementary medicine, and particularly of herbal extracts, on NAFLD patients have received increasing attention in the last few years. The use of this approach has many advantages, including worldwide availability, minimal reported side effects and wide application due to low treatment costs [46].

However, literature data are often inconclusive on this topic, due to the high number of biases found in many trials and to the limited number of studies testing single herbal remedies [47].

In the last two decades, several studies have emphasized the benefits in the NAFLD treatment of Silybum marianum, commonly called milk thistle (MT), a plant native to the Mediterranean area, which has been used for many centuries to treat liver diseases [48,49]. The active complex of MT is a lipophilic extract from the seeds of the plant, and it is composed by three flavonolignan isomers, silybin, silydianin and silychristin, collectively called silymarin.

Studies of patients with NAFLD showed that silymarin treatment was associated with positive changes in insulin resistance and transaminase serum levels [50,51]. Loguercio et al., in a multicenter phase III double-blind clinical trial, showed that MT extracts, after 12 months, led to an improvement of insulin resistance, liver enzymes and liver histology, without any increase in body weight in NAFLD patients [52]. More recently, in a randomized clinical study, we have found out that Mediterranean diet, in association with silymarin and other antioxidants, is able to induce, after six months, significant changes in glucose and lipid metabolism [53].

According to these data, in our cohort, we demonstrated an improvement of BMI, waist and hip circumference, TG, total cholesterol and LDL-C serum level in all patients who followed the Mediterranean diet for a period of six months (Group A and B). The diet also led to the decrease of intra-hepatic fat accumulation, evaluated by the FL index, and of liver stiffness, assessed by TE. However, in the overweight NAFLD Group B patients, who followed the Mediterranean diet in association with BIL antioxidant treatment, we reported the statistical reduction of the HOMA-IR and the TyG index, two surrogate indexes widely used to evaluate insulin resistance.

The changes in glucose and lipid metabolism described in Group B can be explained also by the presence of chlorogenic acid, one component of the BIL complex. Chlorogenic acid is one of the most abundant polyphenols in the human diet. It is contained in coffee, fruits and vegetables and displays many biological properties, such as antidiabetic effects by stimulating glucose uptake in both insulin-sensitive and insulin-resistant adipocytes and by improving early fasting glucose and insulin responses [54]. The metabolic changes observed in our study can be explained by the synergic action of the Mediterranean diet in association with chlorogenic acid and silymarin.

Another component of the BIL complex is protopine, an isoquinoline alkaloid present in Fumaria officinalis, with antioxidant and choleretic properties that inhibit the production of pro-inflammatory cytokines [55]. Our data suggest that protopine could be a potential candidate for NAFLD treatment.
The increase in oxidative stress and free radical production observed in NAFLD lead not only to increased consumption of glutathione, the major intra-cellular antioxidant, but it also reduces the activity of s-adenosyl-l-methionine, the main biological methyl donor and a precursor of glutathione, essential for protecting antioxidant pathways [56]. Recent studies suggest that the reduction of glutathione levels, in combination with lower ATP availability due to mitochondrial deregulation, leads to an unbalance of reactive oxygen species production and to the subsequent progression of hepatic injury [57]. In this context, the administration of reduced glutathione and methionine can help to restore the oxidative balance.

The BIL antioxidant complex treatment alone, not in association with physical activity and a calorie-controlled diet, is not effective in improving insulin resistance. However, our data confirm the possible therapeutic role of this antioxidant complex as a complementary approach to the treatment of overweight NAFLD patients and in particular in the management of insulin resistance in NAFLD-related pathologies.

An important goal for modern hepatologists is to find effective non-invasive diagnostic approaches to NAFLD. In the last two decades, non-invasive diagnostic modalities for NAFLD have been investigated. On the basis of literature data, three non-invasive methods have been employed in the present study for the evaluation of NAFLD. In addition to the US examination, in particular, the FL index and TE have been used to assess respectively hepatic fat accumulation and liver stiffness. The FL index is an accurate and easy to employ predictor score to define steatosis presence that utilizes routine measurements in clinical practice such as a BMI, waist circumference, triglycerides and γGT [36]. In this way, the clinical use of the FL index is useful to identify patients with NAFLD to include in an outpatient lifestyle change program. The data on the reduction of hepatic fat accumulation were also confirmed by the reduction of the Hamaguchi score at the US examination in Groups A and B, compared to Group C.

TE is a non-invasive tool for the evaluation of liver damage that demonstrated good accuracy in quantifying the levels of hepatic stiffness and to define fibrosis, in patients with liver diseases and in particular with NAFLD [37]. This technique is reliable, fast and reproducible, with a good intra- and inter-observer agreement, thus allowing for population-wide screening and disease follow-up.
Finally, our study clearly shows that patients following a balanced diet and taking the antioxidant complex had a more significant attenuation of insulin resistance, hepatic fat accumulation and liver stiffness than patients following the diet alone. These results supported the effectiveness of the BIL complex to reduce liver fatty acid infiltration and its related damages, by positively influencing the mitochondrial function and by reducing oxidative stress.

6. Conclusions
Our study confirms that the Mediterranean diet can improve anthropometric parameters and lipid profile and can contribute to reducing hepatic fat accumulation and liver stiffness. Moreover, the association of this dietetic regimen with antioxidant supplementation can contribute to improving the insulin sensitivity parameters. These data support a possible role of antioxidant supplementation as a coadjuvant therapy in patients with NAFLD.
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