Non-alcoholic fatty liver disease (NAFLD) is a hallmark of steatosis and a major challenge for liver abnormalities and gastroenterology today [1 - 3]. In 1980, NAFLD was introduced to the world for the very first time by Ludwig and his colleagues. In literature, NAFLD plays a vital role in morbidity and mortality along with no signs and symptoms [4]. It encompasses with 4 stages beginning with simple steatosis (see Table 1).

It was estimated that in the general population, 10% to 30% are affected by NAFLD. The clinical investigations of NAFLD always depend on natural history and prevalence worldwide. Subsequently, several researches highlight that basic reason for NAFLD is obesity [5].

Also, Obesity is considered as the gateway for other comorbidities such as malignancies, cardio vascular diseases (CVD), metabolic syndrome (MS), diabetes mellitus (DM), hypertension and insulin resistance (IR) which were the main risk factors for the progression of the condition called NAFLD [14 - 17].

Obesity has become a pandemic concern along with its rapidly progressing prevalence around the world [18]. Obesity is the increased Body Mass Index (BMI). BMI threshold values are used worldwide to categorize individuals in to different groups as shown in Table 2.

BMI reflects excess fat accumulation around the body [19]. In United States, for obesity the BMI cutoff value is defined as 30 Kg/M². It may vary depending on race and phenotypic classifications [20]. According to WHO, Obesity has risen intensely affecting both children and adult. 1/3 of the population is obese. Among them 39% are adults, 41 million are children. This clearly illustrates the progression of obesity around the world [18].

Overall scientific literature shows cases, that the origin of NAFLD is multifactorial [21]. Though the pathology of NAFLD is still unknown, according to many research articles its pathology is defined by two hit hypotheses [11 , 22 , 23]. According to Croke and Sampson (2012), the first hit hypothesis is due to Metabolic syndrome, Insulin resistance and later on to CVD. This leads to the surge in the levels of free fatty acids in liver [24]. The surge, causes the impairment of filtration of fatty acids in liver eventually leads to apoptosis, steatosis and NAFLD [25].

Since one hypothesis is not enough to conclude the pathophysiology of NAFLD, Maheshwari and Thuluvath (2006), states that the first hit hypothesis and its impact on liver leads to many factors such as oxidative stress, diabetes, mitochondrial dysfunction and inflammatory cytokine reactions that defines the second hit hypothesis [26].

Subsequently several researches have stated that these hypotheses which highlights IR, DM, inflammatory cytokines and fatty acid accumulation in liver ultimately from obesity and the correlation with these factors and NAFLD [9 , 23 , 27].

According to Charlton et al (2011) NASH and NAFLD are acknowledged as the main attestation for liver transplantation and also will be anticipated as the governing cause of liver transplantation by 2020.

American journal of gastroenterology reported along with the investigations of majority of population through ultrasound scan testing, it was revealed that NAFLD is progressing worldwide because of obesity and its comorbidities such as metabolic syndrome, diabetes mellitus, insulin resistance and cardio vascular diseases [20 , 28].

“National health and nutrition examination survey” which was conducted in 1988-1994, also emphasized that 1/3 of the population were subjected with NAFLD and among them 90% of subjects were obese [29]. Major risk factor of NAFLD is obesity and this obesity is due to the contribution of multiple factors such as genetic background, lifestyle, food patterns and environmental factors as well [11 , 22]. To analyze the impact of obesity in NAFLD since the concomitance of obesity with IR, metabolic syndrome, T2DM, and inflammatory cytokines, many research articles were based on imaging, laboratory and histological findings. While the patients were ruled out of consuming alcohol or other drugs [30].

Obesity due to excess visceral adiposity along with lectin which is a product and responsible gene of obesity, involves in a dramatic role in modulation of insulin sensitivity whereas leading to insulin resistance and T2DM [1 , 31].

Studies also support that obesity and high calorie intake leads to hepatic insulin resistance. This excess accumulation of fatty acids leads to chronic inflammation around the outlying adipose tissues, which directs to metabolic syndrome and surge in “inflammatory cytokines” such as TNF-alpha, IL-8, IL-6, CRP, MCP and some decreased levels of “anti-inflammatory adipokines” such as IL-10 and adiponectin leading to insulin resistance [31].

Odegaard and Chawla (2008), via testing bacteria and parasite about the innate immune modulation in obesity also supports that this surge in the levels of inflammatory cytokines and decreased levels of anti-inflammatory adipokines is the natural phenomenon in the development of insulin resistance (IR) and gradually to diabetes mellitus (DM).

Fatty acid accumulation in liver underlined obesity also promotes peroxisomal and mitochondrial β-oxidation which enhances microsomal induction of both CYP2E1 and CYP4A1 [31]. Also in the consecutive year [32] sates that this microsomal induction leads to the increased reactive oxygen species in liver promoting mitochondrial dysfunction, steatohepatitis and eventually to NAFLD. According to a study by [33], the mortality in NAFLD patients was due to CVD and malignancy. This study also states that these people were exposed to an obesity risk factor that progressed towards developing T2DM as well.

Table 3 below shows the demographic details of patients with NAFLD around 1980-2003. These studies states that NAFLD is more frequent in females, these studies also showcase with higher prevalence of obesity and the frequent prevalence of T2DM respectively.

The above statistical analysis illustrates a clear picture that, among 505 individuals in the study, 305 were affected with NAFLD. Obesity is in its peak around 64.3% and diabetes around 21% but in those studies, it was also mentioned, there were individuals who developed diabetes as the ultimate reason of obesity [36]. Evidences also show that individuals who were diabetic also developed NAFLD later [4].

A study conducted by Blackett and Sanghera (2016) states that NAFLD is strongly linked with obesity resulting in metabolic syndrome, diabetes and CVD. These trials also emphasize mortality rates of NAFLD are due to developed CVD as a risk factor. It also states that NAFLD is strongly linked with obesity resulting in metabolic syndrome, diabetes and cardio vascular diseases. These trials also emphasize mortality rates of NAFLD patients, due to CVD was high which was also a risk factor of NAFLD [37] (Table 4).

There are so many trials which were tested to analyze the impact of obesity in non-alcoholic fatty liver disease since it also creates so many risk factors such as diabetes and, metabolic syndrome due to hyperlipidemia. As shown in Table 5 below, almost in all trials the above said risk factors were observed simultaneously which gave a clear picture that NAFLD was the ultimate cause of obesity. Since obesity was elicited in a higher percentage of the populations tested [1 , 22].

Statistically 30% of the general population in the world was affected by NAFLD [4 , 47]. Numerous investigations have revealed the possible association of NAFLD for higher rates of mortality today. Nevertheless, obesity underlined risk factors such as CVD, IR, metabolic syndrome, inflammation and hepatic carcinoma, increases the progression of NAFLD [22 , 31].

According to WHO calorie intake and obesity seemed to be double from1980. Rafiq and his colleagues (2009) also state that 39% of NAFLD adult patients around the world were obese. Rinella and Charlton (2016) emphasizes that USA was in the center position of Obesity and NAFLD [21 , 31].

Ongoing studies are focused on the genetic background of NAFLD. Some trials also emphasize that progression of NAFLD is due to variation in PNPLA3 gene which was responsible for breakdown of fats in liver. Due to this variation of PNPLA3 gene it leads to increased production of PNPLA3 and decreased fat breakdown eventually leading to fat accumulation in liver and obesity. Alteration of HIPK 3, AQP9 and TNNI3 also leads to obesity. However, this whole mechanism was not fully understood and the research is still ongoing [30].

In treatment of NAFLD the first line was always based on lifestyle modifications which include exercise and dietary modifications which help the patient to lose weight. It was stated that if the patient reduces the weight by 5% it showed much improvement in the damaged liver due to NAFLD [59 , 60]. Treatment strategies also focused on central appetite suppressants such as Rimonabant, which was an antagonist of cannaboid receptor [61]. Measures are also taken to slow the absorption, drug therapies for insulin resistance, hyper cholesterol levels and diabetes mellitus as well. Different types of bariatric surgeries are also done in patients with NAFLD [48].

Scientists are working on the future development of NAFLD therapy that mainly focus on insulin sensitizing agents that could target PPAR agonists which also reduces the risk of diabetes, bile acid metabolism to reduce the fat accumulation in the liver, induce fat breakdown and filtration of fats in liver. Scientists also focus on anti-inflammatory drugs and anti-fibrotic drugs which could reduce the rate of formation of fibrosis mechanism in liver [28]. Fascinatingly some of the studies also revealed that caffeine in coffee could decrease the rate of liver damage and fibrin formation in hepatocytes [49].

This review analyzed the relationship between obesity and NAFLD. From the trials briefed in this review, it is clearer that NAFLD’s ultimate reason is obesity. Obesity leads to insulin resistance, metabolic syndrome, diabetes, cardio vascular diseases and malignancies which were the major risk factors of NAFLD. This review also emphasizes that 1/3 of the world’s population was affected by NAFLD which is asymptomatic. Pathophysiology of the condition of NAFLD could be explained by two hit hypotheses.

Literature and statistics elicits majority of the NAFLD patients were obese, who later develops its commodities as diabetes and cardiovascular diseases. Statistics also states that NAFLD will be the major reason for liver transplantation in future world. It also states that NAFLD will be the ultimate reason for the hepatic carcinoma by 2020. Moreover, according to the statistical analysis of this review, it shows cases that majority of pediatric population around the world is affected by obesity because of the consumption of junk foods and soft drinks, which leads them to develop NAFLD and comorbidities of obesity. Since treatment and diagnosis were available for NAFLD, much attention should be given to reduce the rate of progression of NAFLD which is a major health risk hidden in the population today.

The authors declare no conflicts of interest regarding the publication of this paper.