**1. Introduction**

Nonalcoholic fatty liver disease (NAFLD) is characterized by the buildup of lipids in the hepatocytes, as evidenced by radiologic or histologic examination. NAFLD occurs without a coexisting etiology of chronic liver diseases, such as medications, alcoholism, or viral hepatitis. The spectrum of NAFLD encompasses two subtypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL is marked by simple mild steatosis, described as an excessive buildup of hepatic triglycerides, typically above 5% of the liver's weight. Steatosis is generally a "benign" condition, and it does not cause liver damage but can pave the way for NASH to develop if not reversed. NASH is more aggressive and develops when steatosis combines with lobular and portal inflammation and liver cell damage in the form of hepatocyte ballooning [1]. The inflammation and liver damage of NASH can cause fibrosis,

or scarring, of the liver and may lead to cirrhosis, in which the liver is scarred and permanently damaged [2]. In some cases, cirrhosis can develop into hepatocellular carcinoma [3] (**Figure 1**). Clinically, it is essential to distinguish between NAFL and NASH, as most NAFLD patients have steatosis without necroinflammation or fibrosis and do not require medical therapy.

NAFLD affects about 25% of the global population [4] and up to 30% in certain regions like the Middle East and South America [5]. NASH has emerged as the Western world's fastest-growing liver transplant indication [6]. The exact etiology of NAFLD remains elusive. However, it is accepted that obesity, type 2 diabetes (T2D), dyslipidemia, and insulin resistance (IR) are its primary causes [7]. The global prevalence of NAFLD among patients with T2D is ~55.5% [8]. Conversely, NAFLD is associated with an increased risk of developing T2D [9]. It is worth noting that NAFLD can also affect lean individuals, who account for 10–15% of all NAFLD cases [10].

The pathophysiology of NAFLD is complex and implicates increased de novo fatty acid synthesis in hepatocytes and lipid retention resulting from reduced hepatocyte apolipoprotein production and β-oxidation [11]. Epidemiological, familial, and twin studies have also provided evidence for an element of heritability of NAFLD [11–13].

An increased emphasis is being placed on discovering novel medicines to prevent, treat, or cure NAFLD due to the disease's skyrocketing incidence and the resulting medical and financial burden. Notwithstanding all efforts, no NAFLD

#### **Figure 1.**

*The spectrum of NAFLD progression and estimated prevalence of the disease stages (adapted from https:// commons.wikimedia.org/wiki/File:NAFLD\_liver\_progression.svg). NAFLD encompasses four stages: 1) simple steatosis (or NAFL), where fat accumulates in the hepatocytes without inflammation, ballooning, or fibrosis. Steatosis affects 20–30% of the world's population. 2) nonalcoholic steatohepatitis (NASH), where there is massive steatosis with indications of hepatocyte injury, i.e. inflammation, ballooning degeneration with or without fibrosis. Some 15–25% of steatotic patients progress to NASH. 3) within 10–20 years, some 5–10% of NASH patients may progress to liver cirrhosis, an end-stage liver disease in which most of the hepatocytes are replaced by collagen. 4) cirrhosis eventually progresses to hepatocarcinoma (HCC), where the liver is unable to regenerate and repair (liver failure), and transplantation is required. HCC affects 2–5% of cirrhotic patients. Factors that cause simple steatosis include calorie-dense Western diets, obesity, T2D, and insulin resistance. Inflammation and hepatocyte apoptosis are factors that contribute to the development of NASH. Liver fibrosis is a transitional phase of NASH that results in the development of liver cirrhosis. Steatosis and NASH/fibrosis could be reversed with lifestyle adjustments, while cirrhosis and HCC are hardly reversible.*

#### *Effectiveness of Lifestyle Interventions for Nonalcoholic Fatty Liver Disease Treatment DOI: http://dx.doi.org/10.5772/intechopen.106445*

pharmacotherapy has yet been approved [5]. At best, physicians can prescribe various medicines to manage the disorders associated with the condition, including hypertension, hypercholesterolemia, T2D, and obesity. Nowadays, weight loss remains the cornerstone treatment for NAFLD. Several randomized controlled trials (RCTs) have shown that ≥5% weight loss improved steatosis, while ≥7% weight loss improved the NAFLD activity score (NAS) [14]. Dietary interventions showed that energy restriction was crucial to improvement in liver fat and transaminase levels. Intensive lifestyle interventions (ILIs) have shown significant success in NAFLD [15]. In the sections below, the limitations of the current NAFLD treatments and the results obtained with ILI-based clinical trials will be discussed.

#### **2. Limitations of current NAFLD treatments**

NAFLD is one of the medical requirements with the greatest unmet potential for pharmacotherapeutic treatments, despite being the most common cause of chronic liver disease globally. NAFLD patients frequently have metabolic comorbidities such as obesity, hyperlipidemia, IR, and T2D [16]. Therefore, the management of NAFLD should consist of treating liver disease as well as these comorbidities. Some of the treatments that have been tried so far include dietary supplements, including polyunsaturated fatty acids (PUFAs), vitamins, and resveratrol, and drugs, including metformin, thiazolidinedione, incretin analogs, glifozines, statins, ACC, FAS, and DGAT1/2 inhibitors, obeticholic acid, SARTANS (telmisartan, valsartan, and losartan), and finally the more invasive bariatric surgery.

Supplementation with polyunsaturated fatty acids (PUFAs) was examined in the management of NAFLD, considering the promising outcomes gained by using a Mediterranean diet (MD) high in PUFAs. A meta-analysis of nine studies involving 355 participants looked at the effect of omega-3 or fish oil supplementation on NAFLD and found that, despite being extremely heterogeneous, some results showed that supplemented patients had significantly lower fatty liver [17]. n-3 PUFA supplementation dramatically reduced liver fat compared to placebo, and it also improved levels of triglycerides, total cholesterol, high-density lipoprotein, and BMI, according to a new meta-analysis comprising up to 22 RCTs and 1366 participants [18]. However, alanine transaminase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transferase (GTT) levels were not significantly improved [18]. Higher blood levels of total n-6 PUFA and linoleic acid were linked to lower probabilities of developing NAFLD in middle-aged and older Finnish people, according to a recent study [19]. The exact mechanism of ω-3 PUFAs' beneficial effect on NAFLD is not fully understood. However, it might result from the combination of their transcriptional repression activity on acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and L-pyruvate kinase, critical hepatic glycolysis, and de novo lipogenesis enzymes [20], as well as their prominent antioxidant, regenerative, and antitumor properties [21]. Despite these promising results, there is a need for well-designed RCTs which quantify the magnitude of the effect of PUFAs supplementation on liver fat as well as the quantities required to achieve a significant effect on liver fat content and improve liver enzyme levels.

Diet and exercise-related lifestyle decisions made by an individual have a major impact on NAFLD. Accordingly, research has highlighted the significance of calorie restriction and macronutrient composition in influencing illness outcomes. However, the liver is also crucial in micronutrient metabolism, and dysregulation of this metabolism may contribute to NAFLD development. Recent studies have highlighted the relation between dietary vitamins and fat accumulation in the liver [22]. A growing number of studies have linked vitamins, notably vitamin E, to NAFLD, and vitamin supplementation has been suggested as a possible therapeutic strategy in treating NAFLD [23]. Changes in the serum levels of vitamin D, vitamin B12, and folate have demonstrated a high link with the severity of NAFLD, and the antioxidant activities of vitamins C and E have been credited with reducing hepatocyte injury. Several biochemical alterations in NAFLD, including the lipotoxic hepatic environment, the altered immune system, the unwarranted inflammation, the oxidative stress, the epigenetic modifications, and the gut dysbiosis, correlate to derangement in vitamins [24]. More carefully planned studies on the human population are still required to establish vitamins' effectiveness and safety as therapeutic agents, despite the attractive prospective choices to improve NAFLD management with vitamins. In fact, high doses of vitamin E were shown to be toxic and could increase the risk of cardiovascular mortality [25].

Resveratrol is a polyphenol in berries, including grapes, blueberries, and blackberries [26], and was suggested as a potential treatment option for managing NAFLD given its anti-inflammatory and antioxidant properties, as well as calorie restrictionlike effects [27]. By reducing lipogenesis and inflammation, resveratrol reduces hepatic steatosis in high-fat-fed mice [28]. For treating NAFLD in humans, a 12-week supplementation of 500 mg of resveratrol and lifestyle modification was superior to lifestyle modification alone [29]. This effect was attributed partially to the attenuation of inflammatory markers and hepatocellular apoptosis. However, the number of participants was small (n = 50 for both arms), and studies with larger cohorts are warranted for validation.

Presently, neither the FDA nor the EMA (European Medicines Agency) has approved a medication for the treatment of NAFLD. Consequently, the agencies concur that any drug provided for therapeutic purposes for NAFLD is regarded as an off-label treatment, and that this therapeutic strategy is addressed with the patient while considering the risk/benefit ratio [30]. Some of the drugs considered relevant for NAFLD treatment are presented in **Table 1**. It is beyond this chapter's scope to discuss each drug's mechanisms of action, but the reader can find ample information in the literature, such as in [101–103].

#### **3. Lifestyle modification in NAFLD treatment**

It is commonly accepted that lifestyle variables, such as an excessive intake of calorie-dense foods and a sedentary lifestyle, are directly related to the pathophysiology of NAFLD, even though the involvement of genetic predisposition in the development of the disease cannot be eliminated. This link is demonstrated by the parallelism between the occurrence of NAFLD and obesity worldwide. Intensive lifestyle interventions, such as dietary changes and regular physical activity that led to significant weight loss, have been the mainstays of NAFLD management and treatment thus far. When successful, lifestyle modifications are far more effective at lowering fibrosis and necroinflammatory alterations in NASH than medications currently being trialed. Therefore, lifestyle modification is considered the main clinical recommendation and the initial step in managing NAFLD. The research supporting the use of lifestyle modification to treat NAFLD/NASH patients' hepatic steatosis and liver histology is examined in this section. Since long-lasting lifestyle changes and

