Clinical characteristic of patients with NAFLD are similar in North America and Europe [31, 33–43]. The average age of NAFLD patients in North America and Europe is 40–50 years old. Contrary to the initial description of NASH, the majority (60–70 %) of patients with NAFLD in the USA are male. Similar gender distribution is reported from Europe except for specific countries such as Lithuania where most of the NAFLD patients are reported to be female [10, 35].

As previously mentioned, most (90 %) patients with NAFLD are found to be overweight or obese. Additionally, age may be associated not only with the development of NAFLD but also its progressive form, NASH [36]. In one particular study, patients who developed NASH were younger, were of Hispanic origin, and had components of metabolic syndrome [37]. These findings were supported in another study where NAFLD/NASH patients were more likely to be male (P < 0.0001); have lower hip-to-waist ratios (P = 0.03); were less likely to be African American (P = 0.06); and had higher levels of alanine aminotransferase (ALT; P < 0.0001), aspartate aminotransferase (AST; P < 0.0001), and serum triglycerides (P = 0.0154), but lower levels of high-density lipoprotein cholesterol (P < 0.0001). In this study, patients with NAFLD who had moderate to severe fibrosis were older (P = 0.0245), were more likely to be male (P = 0.0189), were Caucasian (P = 0.0382), have diabetes mellitus (P = 0.0238), have hypertension (P = 0.0375), and have a lower hip-to-waist ratio (P = 0.0077). Furthermore, they had higher serum AST (P < 0.0001) and ALT (P < 0.0001) levels. After multivariate analysis for predicting moderate to severe fibrosis in NAFLD patients, the significant independent variables were male sex, Caucasian ethnicity, diabetes mellitus, and increased AST and ALT levels (model P value < 0.0001). Based on these findings the investigators developed a predictive model to help clinicians identify patients at high risk for developing or of having advanced fibrosis. This model had a positive predictive value 31.4 % (23.9–39.8 %) and a negative predictive value of 91.0 % (86.7–94.3 %). It is important to note that presence of diabetes alone increased the odds of having advanced fibrosis 25.41 %. This risk incrementally increased as other metabolic syndrome components were added. For example, for patients who had diabetes and hypertension, their risk for moderate to advanced fibrosis was 26.32 %, and if patients also had central obesity (lower hip-to-waist ratio), their odds increased to 26.67 % [38]. It is important to note that in addition to the high prevalence of NAFLD and NAFLD-related fibrosis in diabetics, NAFLD patients with diabetes are also at risk for increased liver-related mortality [38–44].

Although NAFLD may be more common in men, female patients with polycystic ovary syndrome (PCOS) have an increased risk for NAFLD. Researchers have found that the prevalence of both polycystic ovary syndrome and nonalcoholic fatty liver disease rises proportionally to the degree of insulin resistance and the mass of adipose tissue present [45]. The mechanism of action that may cause this association or in fact may actually increase the progression of NAFLD in women with PCOS may be reflected by significantly elevated levels of caspase-cleaved CK18 (M30) suggesting a more proapoptotic environment. This, in addition to the hyperandrogenic state present in PCOS, may cause a suppression of the LDLR (plays a major role in the clearance of apoB- and apoE-containing lipoproteins) receptor sites both in adipocytes and in the liver creating a prolongation of the half-life of VLDL and LDL thereby causing steatogenic effects [45, 46].

In summary, NAFLD in North America and Europe is associated with obesity, diabetes, and other component of metabolic syndrome, including PCOS in female patients. Additionally, being male, being younger (<50 years old), and being of Hispanic descent in the USA increase the risk of having NAFLD. Although lean NAFLD can be seen in these parts of the world, they represent a much smaller cohort with a different clinical profile [37].

As noted previously, risk factors for the development of NAFLD reported from North America and Europe include components of the metabolic syndrome (obesity, dyslipidemia, hypertension, and diabetes/insulin resistance) [31, 41, 47–51]. In this context, visceral obesity is the most important predictor of outcome in NAFLD. In fact, in one study, visceral adipose tissue (VAT) as measured by computed tomography was shown to be strongly associated with NAFLD [(HR) 2.04:1.23–3.38] [52].

The data confirming the association of NAFLD with obesity come not only from tertiary care center but also from population-based studies [2–7, 9, 11–18, 20–67]. In a study from the USA which included 3056 NHANES participants, NAFLD patients were found to be older with a higher BMI, larger waist circumference, and higher sum of skinfolds and had insulin resistance (HOMA > 3.0) or type 2 diabetes [66].

In Europe, similar risk factors for NAFLD (type 2 diabetes, obesity, hypertension, and dyslipidemia) are reported from Europe. In fact, obesity remains the most prevalent risk factor for NAFLD in Europe with 65–90 % in patients with NAFLD being obese or overweight. Data recently reported from 165,000 adults who were included in the report from the European Commission on Fatty Liver Inhibition of Progress (FLIP) suggested higher BMI , waist circumference, weight gain during adult life, and physical inactivity all will increase the risk of each stage of clinically recognized NAFLD (REF). Furthermore, both arterial hypertension and dyslipidemia were highly prevalent in patients with NAFLD, especially in women [67].

Given the interactive association of NAFLD with obesity, both obesity and NAFLD should be considered as similar complex disorders which are related to the environment and genetic predisposition. The environmental factors influencing obesity and NAFLD are related to dietary intake (both number of calories and composition of these calories), activity, degree of stress, cultural issues, and other potential contributors [68]. The genetic predisposition of NAFLD is very also interesting and will be discussed in detail in subsequent chapters.

As noted previously, it is important to mention that NAFLD in the USA may also be present in nonobese patients. In fact, this type of NAFLD may be more common in Asian countries. In the USA, the prevalence of NAFLD among lean subjects was estimated to be only 3.7 %, while this rate was 17.7 % in the obese and overweight individuals [37]. Furthermore, the clinical profile of lean patients with NAFLD is also different where the patients tended to be younger, female, and having a decreased likelihood of having insulin resistance and hypercholesterolemia [37].

As noted previously, patients having a history of diabetes 2 or insulin resistance , dyslipidemia, and hypertension are at increased risk for the development of NAFLD. In one study, the risk of having NAFLD was highest for persons with diabetes (OR, 4.16; 95 % CI, 3.24–5.33), followed by presence of metabolic syndrome (OR, 3.97; 95 % CI, 3.26–4.83). Among other components of metabolic syndrome, central obesity was associated with highest odds for presence of NAFLD (OR, 3.41; 95 % CI, 2.77–4.20) as well as severity of NAFLD (OR, 5.58; 95 % CI, 3.86–8.06). The more component of metabolic syndrome, the higher the risk of NAFLD. In fact, the odds of having NAFLD when three components were present was 9.49 (95 % CI, 5.67–15.90), and when five components were present, the odds was 24.05 (95 % CI, 12.73–45.45) [49].

Given the common risk factors between NAFLD and cardiovascular diseases (CVD), there are increasing reports for higher rates of CVD and CV mortality in NAFLD [1, 49, 69]. A recent study investigating the relationship of NAFLD and cardiovascular disease found that the odds for having a carotid intima–media thickness [cIMT] > 0.8 mm and/or presence of plaques in obese patients with NAFLD was 5.96 (95 % CI, 1.60–22.25; p = 0.008) in men and 8.26 (95 % CI, 4.02–16.99; p < 0.001) in women [69]. In addition to high rate of CVD, there is also an increased rate of CV mortality. Although liver disease has been reported as the third leading cause of death among persons with NAFLD, cardiovascular disease and malignancy are the two top causes of death in NAFLD patients [34]. In one particular long-term follow-up study (mean follow up time of 18.5 years), approximately 60 % of the patients with NAFLD had died with the most frequent cause of death cited as coronary artery disease (30 %), followed by nonliver malignancy (18 %) and then liver-related mortality including hepatocellular carcinoma (15 %) [38, 44].

The strong association of DM and metabolic syndrome with NAFLD has also been reported from Europe. In a prospective study of 230 patients from nine centers, metabolic syndrome was found in the majority of patients (53 %) with 54 % of the patients being male with a mean age of 49.4 ± 13.9 years and a mean BMI of 30.6 ± 4.6 kg/m². In 16 % of the patients, undiagnosed diabetes was discovered. For the patients (51 %) who had a liver biopsy, fibrotic staging was significantly more severe in patients with metabolic syndrome (2.43 ± 1.25 vs. 1.73 ± 1.18, p < 0.001). A subgroup of patients with GGT > 5 × ULN were significantly older (55.9 vs. 47.64 years, p = 0.02), were more frequently diabetic (53 % vs. 23 %, p = 0.01), and had more advanced fibrosis (3.42 vs. 1.08, p = 0.0080 [41].

Another interesting study from Europe was initiated in Italy. The Italian Society for the Study of Atherosclerosis (SISA) in 2005 started a research project aimed to study NAFLD. Using ultrasound (US) in nondiabetic subjects, the researchers set out to determine the prevalence of NAFLD, its associated risk factors and prevalence of hypertransaminasemia, and its possible determinants. NAFLD prevalence was 0.78. Their initial results showed that men with hepatic steatosis (as compared to men without steatosis) were younger (P < 0.05) and had higher triglycerides (P < 0.03), higher homeostasis model assessment insulin resistance (HOMA-R) (P < 0.003), and increased visceral fat thickness (P < 0.0001). Furthermore, women with steatosis showed higher triglycerides (P < 0.05), HOMA-R (P < 0.04), VFT (P < 0.0001), and younger age (P < 0.05). Multivariate analyses found that visceral fat thickness (P < 0.0001), HOMA-R (P < 0.02), and triglyceride to HDL ratio (P < 0.05) were associated with the severity of NAFLD. Age (P < 0.05), log ratio of triglycerides (P < 0.005), and visceral fat thickness (P < 0.01) were also associated with higher ALT. The prevalence of steatosis was reported to be the highest reported in patients with metabolic syndrome. These investigators concluded that due to the exclusion of severely obese and diabetic patients, their findings highlight the prominent role that alterations of lipid metabolism play in the pathogenesis of NAFLD [17].

Finally, in a recent study from Finland, the prevalence of NAFLD in young Finnish was 29 % in overweight/obese and 5 % in normal weight individuals. The independent correlates were waist circumference, ALT, BMI, male gender, triglycerides, systolic blood pressure, and insulin resistance [70].

Although there seems to be a genetic component to the predisposition to NAFLD, diet and activity play a major role. It seems the Western diet high in calories and refined sugar and fructose may play a role in the development of obesity and associated NAFLD. Nevertheless, systematic assessment of diet and activity at the population level in the USA is scarce [71–82].

Other dietary components may also play a role. In one large population-based study using 4 cycles of NHANES data from 2001 to 2008, investigators studied dietary intake questionnaires which listed 62 nutritional components. Univariate analysis found that 38 % of the nutritional components were significantly different between patients with NAFLD and those without NAFLD where patients with NAFLD. After multivariate analysis adjusting for demographic confounders (age, gender, ethnicity), Hispanic race, being male, being obese (BMI > 30), and drinking less caffeine were associated with NAFLD. Although the issue is controversial and the mechanism is not entirely clear, drinking caffeine in the form of coffee actually seems to have a protective effect on the development of NAFLD. This is possibly due to the suppressive effect that coffee has on hyperglycemia by improving insulin sensitivity through the reduction of inflammatory cytokine expression [71, 72].

It is important to note that diet can have an impact both by being responsible for the development of central obesity as well as a direct effect on the inflammatory environment of patents with NAFLD. In fact, one of the most exciting areas of research in NAFLD is the contribution of visceral adipose tissue (VAT) to the development of NAFLD. In fact, the white adipose tissue of VAT is thought to be an endocrine organ that produces adipokines and cytokines responsible for the development of an inflammatory milieu contributing to pathogenesis of NASH, CVD, and other complications of visceral obesity [73]. In addition to VAT being responsible for the inflammatory milieu of NAFLD, there is also some contribution of diet itself on these proinflammatory fat cytokine/chemokine expression within the liver. Animal studies have suggested that diets high in saturated fat, fructose, and cholesterol as well as a specific combination of carbohydrates and fats (starch/oleate) set off a cascade of molecular metabolic derangements including insulin resistance and activation of the miRNA resulting in a more severe form of NAFLD or NASH [74–76]. In addition to adipocytokines, oxidative stress also plays a major role in the development of NAFLD. Recent findings suggest that the extent of hepatocyte ballooning reflect the severity of oxidative DNA damage and accumulation of DNA methylation in NAFLD [77, 78]. In fact, the impact of diet on the oxidative stress cycle has been suggested [78, 79]. Diet can influence microRNA which is involved in the pathogenesis of NAFLD. In fact, animals exposed to a high fat diet showed a dysregulation of miRNA-451 leading to development of NAFLD and fibrosis [77, 78, 80, 81]. All of these mechanisms may be related to the “additional” effect of diet on the development and progressive nature of NAFLD.

In regard to physical activity, patients with NAFLD seem to have low activity levels compared to controls. In fact, patients with both NAFLD and diabetes experienced the lowest level of physical activity [82].

In summary, NAFLD is associated with components of metabolic syndrome. Although genetic predisposition probably plays a role, it only explains a small portion of the increased risk. In this context, the influences of environmental factors are significantly more important. Metabolic syndrome is quite frequent in the general population, although its prevalence varies considerably according to the criteria used for its definition. Additionally, metabolic syndrome is associated with NAFLD, with the WHO definition being the best to determine its presence, probably because of the inclusion of insulin resistance as a main component. Unification of criteria for metabolic syndrome is needed to adequately compare its prevalence and relationship with NAFLD in different population groups [31].