In recent decades, non-alcoholic fatty liver disease (NAFLD) prevalence has increased into pandemic dimensions, affecting about one-third of western populations, probably due to the increasing prevalence of obesity and metabolic disease ^[1][2][12,13]. NAFLD represents a spectrum of diseases ranging from simple steatosis to NASH and, finally, cirrhosis. Although approximately only 10–20% of patients with NAFLD progress to NASH, and 15–20% of patients with NASH progress to cirrhosis, the absolute numbers are not negligible due to the wide prevalence of NAFLD ^[3][14]. The complications of NAFLD can be divided into hepatic and extra-hepatic. The hepatic complications of NAFLD include progression to cirrhosis. Studies have shown that the progression from steatosis to fibrosis can take 14 years, while the progression from NASH to cirrhosis may take 7 years ^[4][15]. Decompensated cirrhosis which can be manifested as hepatic encephalopathy, ascites or gastrointestinal bleeding secondary to esophageal varices, occurs annually at a rate of 3–4% in patients with compensated cirrhosis ^[5][16]. A meta-analysis of 13 studies showed higher mortality rates in patients with cirrhosis than in patients without fibrosis ^[6][17]. Hepatocellular carcinoma (HCC) is another serious complication of NAFLD, with poor outcomes and limited therapeutic options. The majority of NAFLD-related HCC cases occur in the setting of cirrhosis. However, about 20% of the cases occur in non-cirrhotic livers. An important risk factor for developing HCC is the presence of diabetes and metabolic syndrome ^[7][8][18,19]. A recent study revealed that the lack of fibroblast growth factor 21 (FGF21), which has anti-inflammatory effects, enhances the progression from NASH to HCC ^[9][20]. In addition to HCC, there is a higher incidence of extra-hepatic malignancies, particularly colorectal and uterine cancers, in which the risk is increased twofold ^[10][21]. It is not surprising that cardiovascular risk is increased in the presence of NAFLD since both of them share many risk factors, including dyslipidemia, obesity, hypertension and diabetes. A key factor in the development of both diseases is insulin resistance which contributes to the lack of lipolysis suppression, thereby increasing free fatty acids (FFA) in the circulation, ending up accumulating in the liver and blood vessels ^[11][12][13][22,23,24]. Cardiovascular complications are the most common cause of death in NAFLD, accounting for nearly 40% of the cases ^[14][25]. NAFLD is a risk factor for severe disease and liver injury ^[15][16][26,27].

2. Metabolic Profile of NAFLD

Much research on NAFLD has been done, but no accurate mechanism has been described yet. A good understanding of the metabolic and biological mechanisms of this situation could help peopleus in developing good predictors and markers. Several theories were suggested in the context of NASH development. The “double-hit” hypothesis suggests that the first insult or the “first hit” is characterized by lipid accumulation in the liver, resulting in steatosis, which enhances the liver’s susceptibility to the “second hit” characterized by inflammation and necrosis induced by oxidative stress and proinflammatory mediators ^[17][18][66,67]. The simplistic “double-hit” theory was substituted by a more complex theory, the “multiple-hit” hypothesis, which has become more accepted recently, representing the interaction of multiple metabolic and genetic factors leading to the development of NASH. Such “hits” include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors ^[19][68].

2.1. The Role of Adipose Tissue in NAFLD

Obesity is associated with increased prevalence and severity of NAFLD. The adipose tissue functions as an endocrine organ secreting adipokines and cytokines ^[20][69]. Adiponectin is anti-inflammatory, and its levels are inversely associated with cardiovascular risk factors and visceral adiposity. It increases free fatty acid (FFA) oxidation and decreases gluconeogenesis resulting in decreased liver steatosis. Furthermore, it acts as a pro-inflammatory inhibitor, opposing the effects of tumor necrosis factor (TNF)-α and interleukin (IL)-6 ^[17][21][22][66,70,71]. Leptin secretion is directly proportional to the white fat mass. Circulating leptin levels are higher in patients with NAFLD than in healthy patients, and higher levels are associated with the severity ^[23][72]. Leptin has different effects depending on the stage of the disease. At early stages, it acts as an anti-steatotic and increases insulin sensitivity. At more advanced NAFLD stages, it has an unfavorable effect by promoting inflammation ^[24][25][73,74]. Pro-inflammatory cytokines are immunoregulatory cytokines that favor and enhance the process of inflammation ^[26][75]. Fat accumulation in the liver mediates cytokine production in hepatic cells. These cytokines induce inflammation, necrosis, cell apoptosis and mediated liver stiffness and fibrosis. Pro-inflammatory cytokines are also secreted by adipose tissue and are involved in the recruitment and activation of macrophages, a process that leads to chronic low-grade inflammation and the development of insulin resistance and cardiovascular diseases ^{[24][25][26][27][28]}[73,74,75,76,77].

2.2. Lipotoxicity in NAFLD

Lipotoxicity is a leading factor in the development and progression of NAFLD and NASH. The total amount of triglycerides stored in the liver cells is not the main determinant of lipotoxicity ^[27][28][76,77]. Specific lipid classes, especially free fatty acids (FFA), which accumulate in hepatocyte cytoplasm, act as damaging agents via multiple mechanisms. These include activation of death receptors, modification of mitochondrial function and oxidative stress, which lead to the progression from NAFLD to NASH, its inflammatory form. Insulin resistance plays a major role in lipotoxicity by enhancing lipolysis in adipose tissue and increasing the amount of circulation FFAs ^[27][28][76,77].

2.3. The Role of Glucose in NAFLD

High-carbohydrate diets and NAFLD are strongly correlated ^[29][78]. Hyperglycemia is strongly associated with oxidative stress ^[30][79], leading to chronic inflammation and insulin resistance ^[31][80]. Insulin resistance in NAFLD is characterized by reductions in whole-body, hepatic, and adipose tissue insulin sensitivity. The mechanisms underlying the accumulation of fat in the liver may include excess dietary fat, increased delivery of free fatty acids to the liver, inadequate fatty acid oxidation, and increased de novo lipogenesis. Insulin resistance may enhance hepatic fat accumulation by increasing free fatty acid delivery and by hyperinsulinemia to stimulate anabolic processes. The impact of weight loss, metformin, and thiazolidinedione, all treatments aimed at improving insulin sensitivity, as well as other agents such as vitamin E, have been evaluated in patients with NAFLD and have shown some benefit. However, most intervention studies have been small and uncontrolled ^[32][81].

3. Risk Stratification

In light of the increased morbidity and mortality in NAFLD, and considering its wide prevalence, many efforts are put into identifying patients at risk for disease progression to enable early intervention and to prevent the development of cirrhosis ^[33][82]. Several algorithms were developed to screen NAFLD patients, each relying on different parameters (Figure 1) ^[34][83]. The European Association for Liver/-Diabetes/-Obesity Guidelines (EASL-EASD-EASO) uses the NFS and FIB-4 scores, while the German National Guidelines use LSM to guide the management of NAFLD patients ^[33][82]. NAFLD has almost reached epidemic proportions worldwide. Wide dissemination of current concepts on NAFLD and extensive collaboration between physicians, governments, non-governmental organizations, and the pharmaceutical industry is urgently needed to advance a NAFLD public health policies agenda that allows peopleus to address this disease more holistically in a society-wide manner ^[31][80].