Strategie dietetiche nei pazienti con steatosi epatica non alcolica: dalle evidenze alla pratica clinica quotidiana, una revisione sistematica

INTRODUCTION

Non‐alcoholic fatty liver disease (NAFLD) affects 30% of the global population. , , , The rising global burden of NAFLD parallels the increasing prevalence of type 2 diabetes mellitus (T2DM) and obesity, resulting in high healthcare resource utilization and costs. , NAFLD is a spectrum of liver diseases ranging from liver steatosis to non‐alcoholic steatohepatitis (NASH), and fibrosis, which may lead to cirrhosis and hepatocellular carcinoma. Furthermore, NAFLD is associated with an increased risk of incident T2DM, chronic kidney disease, extrahepatic cancers, and cardiovascular morbidity and mortality, , , , underscoring the multi‐systemic pattern of this disease. Similarly, evidence suggests that the visceral adipose tissue (VAT), one of the hallmarks of NAFLD, is associated with increased atherosclerosis and cardiometabolic risk, , , , while its reduction is correlated with hepatic histologic improvements, independently of liver fat reduction. Therefore, considering the aforementioned findings, NAFLD management requires a multidisciplinary care team to mitigate negative liver‐related and extra‐hepatic‐related outcomes.

Currently, no pharmaceutical treatments are approved for NAFLD therapy. Therefore, comprehensive lifestyle modification interventions, including calorie restriction (CR) and increased energy expenditure, remain the cornerstones of NAFLD treatment. , Although the amount of weight loss is the most important determinant of liver histological feature outcomes , and the most well‐validated treatment, healthy eating patterns and dietary composition can also have a beneficial impact on the risk of new‐onset NAFLD, and can provide additional benefits such as the reduction of cardiovascular disease risk, , improvements in metabolic outcomes, , and reductions in mortality. However, only a few patients reach the significant and sustained weight loss needed for a positive effect on liver damage, and maintaining long‐term adherence to lifestyle modification remains a challenge.

The evidence in the literature is growing with regard to the specific dietary patterns associated with greater cardiovascular and metabolic benefits, but is scarce regarding strategies to adjust the pattern to individual patients based on socio‐economic, cultural background, and personal preferences for promoting long‐term adherence. Recent research has demonstrated that the Mediterranean diet (MD) is beneficial for the prevention of cardiovascular disease, and the management of NAFLD. , However, various other dietary strategies exist that are less well studied in the area of NAFLD. This systematic review aims to summarize the effects of different dietary strategies and exercise interventions on liver function in patients with NAFLD.

METHODS

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines.

### Data sources and search strategy

We searched four databases, MEDLINE, EMBASE, Web of SCIENCE, and Cochrane Central Register of Controlled Trials (CENTRAL), from 2010 to September 2022. The formulation of search terms was designed and conducted jointly by a medical librarian with study investigators. The list of search terms is provided in Supporting Information . Reference lists of previously published systematic reviews and meta‐analyses were examined to find additional relevant studies. Only articles published in English were considered.

### Eligibility criteria

We included only randomized controlled trials (RCTs) and clinical controlled trials in this systematic review. The inclusion criteria were as follows: (a) adult patients (>18 years old); (b) dietary and exercise interventions on surrogate markers of NAFLD; (c) interventions: MD intervention and/or CR intervention and/or time‐restricted eating and/or low‐fat diet (LFD) and/or low‐carbohydrate diet (LCD) and/or physical activity (PA); (e) surrogate markers of NAFLD: histology (NAFLD activity score [NAS], individual scoring of ballooning, lobular inflammation, and steatosis) and/or liver function tests (LFTs) (including alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), and/or non‐invasive markers of liver fibrosis (NAFLD fibrosis score, fibrosis 4 index [FIB‐4], elastography, FibroScan‐AST [FAST] score), and/or non‐invasive markers of liver steatosis evaluated either by imaging: controlled attenuation parameter (CAP), magnetic resonance imaging or spectroscopy (MRI/MRS) proton density fat fraction (PDFF), ultrasonography, or serologically: fatty liver index (FLI), hepatic steatosis index (HIS); (f) minimal sample size of 30 patients (total); (g) human studies.

The following were exclusion criteria: (a) lab‐based feeding trials; (b) animal studies; (c) in vitro studies; and (d) other study designs.

Primary outcomes included surrogate markers of NAFLD (histological features and/or LFTs, and/or non‐invasive assessment of liver fibrosis and steatosis) and secondary outcomes included total body weight loss (TBWL), waist circumference, quality of life, cardiometabolic parameters (blood pressure, lipid profile, cardiovascular risk) and glycated hemoglobin (HbA1C).

Two reviewers (AH, MA) independently assessed relevant studies for eligibility. The final study selection was reached by a mutual agreement between the two reviewers.

RESULTS

A total of 4374 studies were identified, 20 of which were duplicates. After title and abstract review, 241 studies were scanned for full‐text review. The full‐text review resulted in 61 studies, of which 10 were systematic reviews and meta‐analyses used for checking reference lists. Finally, 51 studies were included in this narrative systematic review (Figure ).

Table outlines the characteristics and efficacy outcomes of different lifestyle interventions in NAFLD.

Table depicts the characteristics and efficacy outcomes of different lifestyle interventions on liver histology in NAFLD patients.

### Mediterranean diet (with or without calorie‐restriction)

MD is characterized by a high intake of olive oil, vegetables, fruits, nuts, legumes, whole grains, fish, and seafood, while reducing the intake of red meat (mainly processed meat), added sugars, and refined carbohydrates characterized by a high glycemic index, all of which lower nutrients and fiber content resulting in low nutritional values.

MD is designed to have a low intake of saturated fat versus a high intake of mono‐unsaturated fat and omega‐3 poly‐unsaturated fat (Figure ).

Due to the fact that weight loss achieved by a CR LFD (Figure ) along with exercise has been shown to provide resolution of NASH and even regression of fibrosis when TBWL is >10%, several RCTs , have been conducted to compare the effects of the two aforementioned diets in NAFLD patients. In two short‐term RCTs , of 12‐week dietary interventions (MD vs. LFD), no significant differences in terms of liver steatosis and metabolic outcomes between the two strategies were demonstrated. Hepatic steatosis (evaluated by MRS), was significantly reduced only in the LFD group in the MEDINA trial. However, the Framingham risk score (a validated tool for evaluating 10‐year cardiovascular risk ) was only significantly improved in the MD intervention, and there was a greater adherence to the MD compared with the LFD.

In order to determine the long‐term effect of these two interventions, an 18‐month RCT was performed among patients with central obesity ( N = 278, 53% had NAFLD) assessing the effects on liver fat content and visceral adiposity of four different lifestyle modification strategies: (i) isocaloric LFD with/without moderate PA, and (ii) isocaloric MD‐low carbohydrate (LC) diet with/without moderate PA. This study showed that, independent of weight loss, PA (with either diet) had a significantly greater effect on VAT, whereas the MD‐LC diet was superior to LFD in terms of liver fat improvement. Similarly, studies , , comparing the isocaloric MD diet to standard of care (healthy lifestyle advice) have also observed significant decreases in liver fat content, non‐invasive markers of liver fibrosis, and LFTs.

Since CR plays a role in weight loss, personalizing the dietary pattern of an MD diet to ensure greater adherence and weight loss could be advantageous. In this regard, two RCTs , have recently assessed the influence of increasing meal frequency (7 meals/day) of a MD‐LC calorie‐restricted dietary intervention along with PA on liver surrogate outcomes in NAFLD patients. Although this intervention induced significant improvements in liver steatosis and LFTs, no significant difference was found between the higher meal frequency MD diet, the classic MD intervention (5 meals/day), and the control group who was advised to follow a healthy lifestyle diet. Several other studies , , , assessed CR MD diet strategies in the setting of NAFLD, and showed that this strategy was associated with improvements in non‐invasive markers of liver fibrosis, steatosis, and LFTs.

On the other hand, it has been recently shown that polyphenol intake (abundant in food such as berries, nuts, coffee, tea, and whole grains) improves not only glucose and lipid metabolism , but also may have a protective effect on NAFLD. The DIRECT plus RCT trial assessed the effect of a green MD diet enriched with polyphenols (28 g/day of walnuts, 3–4 cups per day of green tea, 100 g per day of Mankai strain and a green shake) combined with PA on liver steatosis and liver function tests as compared to either a classic MD diet (with PA) or a control group following the standard of care. Both MD groups were restricted in processed and red meat. Two hundred and ninety‐four patients (of which 62% had NAFLD) were included and followed for 18 months. The modified green MD diet led to greater hepatic fat loss (−38.9%) as compared to MD (−19.6%, p = 0.035) and the control group (−12.2%, p < 0.001), adjusted for weight loss. Interestingly, the following factors were independently associated with greater hepatic fat loss: high intake of Mankai and walnuts, reduction of red and processed meat consumption, improved serum folate and adipokine/lipid biomarkers, changes in the microbiome composition (beta‐diversity), and specific bacteria ( p < 0.05 for all).

Lastly, a comprehensive CR MD web‐based structured motivational program implemented for 24 months did not seem to be inferior to a group‐based MD intervention (5 weekly meetings) in terms of reduction of liver fibrosis (FIB‐4) and steatosis (FLI). This strategy is likely more suited and tailor‐made for younger patients.

### Calorie restriction

Numerous studies , , , , , , , , , , , , have evaluated the effect of a CR diet with or without PA on NAFLD. In most of these studies, the CR consisted of a 500–1000 kcal deficit of total energy requirements and was usually adjusted to body weight. Although the studies were heterogeneous regarding intervention and outcome assessment modalities, there was compelling evidence supporting a dose‐response relationship between the degree of CR and improvements in liver histological features and weight loss.

### Time‐restricted eating

Intermittent fasting (IF) is deemed to be associated with several positive metabolic benefits by depleting the body's glycogen stores and activating lipolysis within adipocytes. Consequently, several signaling pathways are activated (such as peroxisome proliferator activated receptor alpha [PPAR‐α] and activating transcription factor 4 [ATF4]), resulting in improvement in insulin resistance and inhibition of hepatic lipogenesis. , , , Different modalities of IF exist daily time‐restricted feeding regimen (TRF) (18‐h fasting period and 6‐h eating period), alternate‐day fasting (ADF) (24‐h of fasting at 25% of baseline energy), and the 5:2 intermittent regimen, which consists of fasting 2 days a week (intake of 500 calories). The effect of an ADF regimen in NAFLD patients has been compared to TRF (16 h of fasting) and a control group where patients consumed 80% of their daily energy requirement. After 12 weeks, both ADF and TRF were associated with a reduction in weight, fat mass, and serum triglycerides. However, there was no change in terms of liver stiffness, albeit, regression of liver fibrosis usually occurs at later stages. Conversely, the 5:2 intermittent regimen also administered for a short‐term (12 weeks) induced reductions in liver stiffness and steatosis as compared to a control group (standard of care), but similar to a LCD following an equal weight reduction of about 7 kg. Similar findings were found in a retrospective comparative study comparing NAFLD patients who had fasted during Ramadan to a control group. These discrepancies regarding liver fibrosis could be explained by the fact that these studies used surrogate endpoints of liver fibrosis (liver stiffness or NAFLD fibrosis score) and, therefore, a reduction does not particularly correlate with histological fibrosis stage reduction if the value is still within the same cut‐off range.

### Low carbohydrate diet‐Low fat diet

Several studies , , , , , , sought to compare the effectiveness of LCD and LFD (Figure ) on surrogate liver outcomes for NAFLD. Similar to time‐restricted eating studies, most of these studies were of short‐term course and LCD seemed to be superior to LFD in terms of liver fat reduction and LFTs, adjusted for equal weight loss. Nevertheless, these studies presented several drawbacks such as small sample size, various LCD dietary type compositions, and different modalities for assessing liver fat content, making it difficult to draw any convincing conclusions. Results from a long‐term study comparing LCD to LFD diets showed a decrease in ALT in both interventions. This was also confirmed by a recent meta‐analysis showing that there was no significant difference between the LCD and LFD diets on liver fat reduction and LFTs in NAFLD patients.

### Very low carbohydrate ketogenic diet

Very low carbohydrate ketogenic diet (Figure ) (VLCKD) is characterized by a low intake of carbohydrates (<10% of total daily energy, <20–50 g/day), 1.2–1.5 g of protein/kg of ideal body weight (hence preserving lean body mass), and a high fat macronutrient composition (70%–80% of total daily energy). A few short and small studies , have evaluated the effect of VLCKD on NAFLD compared with a standard CR diet and found significant reductions in liver fat content. Despite the substantial weight loss induced in a short‐term course by this type of dietary approach, its long‐term maintenance is not sustainable or recommended due to the lack of long‐term data on efficacy and safety.

DISCUSSION

NAFLD is likely a result of the interplay between genetic predisposition, and environmental, behavioral, and health factors including diet, T2DM, and obesity (Figure ). , Compelling evidence suggests that overconsumption of added sugars (especially fructose containing sugars), , and saturated fat, , or specific foods such as processed/red meat, ultra‐processed food, and sugar sweetened beverages is associated with an increased risk of developing NAFLD. In addition, sugar‐sweetened beverage consumption is strongly linked to the risk of hepatocellular carcinoma. ,

Since dietary pattern and composition drive NAFLD development, different dietary strategies, highlighted in this review, have been studied in order to determine which approach could be more beneficial in NAFLD patients. To date, the most studied dietary intervention is the MD diet, which combines moderately reduced intake of carbohydrates and minimal consumption of added sugars, and has been found to be achievable and acceptable by patients. However, despite the convincing results of MD diet effectiveness on surrogate markers of NAFLD, the impact of this dietary strategy on liver histological features as well as clinical outcomes of NAFLD still needs to be addressed. Furthermore, economical, geographical, and cultural barriers could jeopardize adherence to this dietary intervention, which emphasizes the importance of personalizing our approach to not only the patient's needs but also their socio‐economic status. Ultimately, as previously mentioned, CR and increased energy expenditure remain the cornerstones of NAFLD treatment. Therefore, the approach of lifestyle modification should be holistic (Figure ), encompassing recommendations regarding dietary pattern and composition but also promoting PA and behavioral strategies to ensure greater adherence and benefits in terms of mortality. In this regard, comprehensive structured web‐based programs maintaining NAFLD awareness , (Figure ) could not only be an asset for managing attrition, and hence, adherence, but also a way to reduce cost and health care resource utilization. Some patients will find web‐based interventions convenient and some patients will need the in‐person interventions or a combination of both. Other actions for increasing compliance to lifestyle modification are summarized in Figure .

PERSPECTIVES AND CONCLUSION

Since NAFLD is a chronic disease requiring life‐long therapy, there are several unmet needs to address in order to better characterize an effective diet and lifestyle intervention in NAFLD patients. Considering that NAFLD is a heterogeneous disease, patient stratification is crucial for establishing a personalized and tailored dietary approach. Nutrigenomics and nutrigenetics could be a promising tool to decipher the effect of different dietary strategies on the modulation of different NAFLD variants. Additionally, more robust data are needed in the assessment of dietary intake and in the characterization of the interventions associated with greater adherence. Long‐term longitudinal studies will likely help to fill these knowledge gaps.

In conclusion, lifestyle modification comprising CR, increased PA, and changes in dietary composition remain the cornerstones of NAFLD management. Since most dietary and sedentary lifestyle environmental risk factors are modifiable, health policies are essential to tackle obesity, unhealthy eating, and sedentary lifestyle. Finally, multidisciplinary care teams led by primary care healthcare providers should be implemented in order to provide to best structured care to NAFLD patients.

CONFLICT OF INTEREST STATEMENT

The authors have no conflicts of interest to declare.

Supporting information