Non-Alcoholic Fatty Liver Disease and Extrahepatic Cancers: A Wolf in Sheep’s Clothing?

Non-alcoholic fatty liver disease (NAFLD) is now considered the main driver and leading cause of chronic liver disease globally. The umbrella term NAFLD describes a range of liver conditions closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia. At the same time, several malignancies, including hepatocellular carcinoma and colorectal cancer, are considered to be common causes of death among patients with NAFLD. At first, our review herein aims to investigate the role of NAFLD in developing colorectal neoplasms and adenomatous polyps based on the current literature. We will also explore the connection and the missing links between NAFLD and extrahepatic cancers. Interestingly, any relationship between NAFLD and extrahepatic malignancies could be attributable to several shared metabolic risk factors. Overall, obesity, insulin resistance, metabolic syndrome, and related disorders may increase the risk of developing cancer. Therefore, early diagnosis of NAFLD is essential for preventing the progression of the disease and avoiding its severe complications. In addition, cancer screening and early detection in these patients may improve survival and reduce any delays in treatment.


Introduction
Non-alcoholic fatty liver disease (NAFLD) is a term used for a range of liver conditions, including simple steatosis and non-alcoholic steatohepatitis (NASH), which may eventually progress to liver fibrosis, cirrhosis, and cancer [1,2]. Excessive hepatic fat accumulation in patients without significant alcohol consumption represents a major cause of liver dysfunction and chronic liver disease worldwide [3][4][5]. In addition, NAFLD appears to be associated with insulin resistance, metabolic syndrome, diabetes mellitus and obesity [6]. Due to its increasing prevalence, particularly in Western countries, the development of invasive and non-invasive diagnostic tools and the adoption of novel treatment options have been the focus of increased attention in order to improve the prognosis of the disease.
There is a substantially increased risk for overall and liver-related mortality among NAFLD patients [7]. NAFLD is usually a silent liver disease without causing any symptoms. However, it may lead to severe liver-related and extrahepatic complications, such as cardiovascular disease and malignancies [8,9]. To date, accumulated evidence shows a potential association between NAFLD and the incidence of several extrahepatic cancers [10]. As a result, the efforts to better understand the mechanisms linking NAFLD with the risk of developing some malignancies have raised great interest.
Any association between NAFLD and extrahepatic cancers might be attributable to shared metabolic risk factors [11]. The relationship between NAFLD, colorectal cancer (CRC), and adenomatous polyps has been thoroughly investigated during past decades. However, the exact mechanisms correlating NAFLD with CRC, and its precursor lesions, are not entirely understood yet. Furthermore, several researchers have attempted to investigate the association between NAFLD and other extrahepatic neoplasms, including esophageal, gastric, biliary tract, pancreatic and breast cancer [11,12].
A comprehensive literature search in PubMed up to January 2022 was conducted to identify recent studies (mainly during the last 12 years) that analyzed the relationship between NAFLD and different extrahepatic malignancies. We also examined the reference lists of the included articles in order to find additional relevant reports. In fact, the current review focused on all relevant English articles that provided information on the association between patients previously diagnosed with NAFLD and/or extrahepatic cancers.
Our research herein aims to help understand the key issues related to the development and progression of NAFLD. Based on the current literature, CRC is the most well-studied form of cancer observed among NAFLD patients. It also represents one of the most common causes of cancer-related deaths. At first, our objective was to thoroughly examine the relationship between NAFLD, colorectal carcinomas and their precursor lesions. Then, we investigated the association between NAFLD and other extrahepatic malignancies, suggesting the necessity for screening, particularly in cases with high cancer risk. However, further studies are still required in order to shed some light on the role of NAFLD in the above-mentioned forms of cancer. Importantly, NAFLD seems to be an underestimated multisystem disease with far-reaching consequences commonly overlooked by the general population.

Overview of Non-Alcoholic Fatty Liver Disease (NAFLD)
First described in the 1980s, NAFLD as an umbrella term encompasses a wide range of liver conditions from simple steatosis to NASH, which can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma [1,2]. Over the past few decades, NAFLD has become an alarming public health concern due to its increasing prevalence, particularly in Western countries, reaching global epidemic proportions in both adults and children [13,14]. Indeed, NAFLD has emerged as a major etiology of chronic liver disease worldwide. It is expected to become the most rapidly growing indication for liver transplantation within the next few years [3].
NAFLD is defined by excessive fat deposition in the liver with the presence of intracellular triglycerides in more than 5% of hepatocytes in patients without significant alcohol consumption (<30 g/day for males, <20 g/day for females) [4,5]. Furthermore, other secondary causes of steatosis, including viral, drug-induced, alcoholic liver disease or acute fatty liver of pregnancy, are excluded [15,16]. As a spectrum of liver disease, NAFLD appears to be closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia [6]. Indeed, a growing number of recent studies suggest a significant association between NAFLD, metabolic syndrome and its components [6,17]. However, despite the "chicken-and-egg" conundrum regarding the primacy of either metabolic syndrome over NAFLD or NAFLD over metabolic syndrome, NAFLD is now recognized as the hepatic manifestation of metabolic syndrome [17][18][19].
At the same time, there have been global efforts to raise awareness of the disease by changing the definition and nomenclature of NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD). Specifically, an international panel of experts from 22 countries proposed new definition criteria for diagnosing MAFLD, considering the disease heterogeneity and the underlying metabolic factors as the key contributors to the disease progression [20]. MAFLD is diagnosed in patients with evidence of hepatic steatosis (based on imaging, histopathological examination or blood biomarker testing) and the presence of at least one of the following three metabolic criteria: obesity/overweight, established type 2 diabetes mellitus (T2DM) or metabolic dysregulation [20] (Figure 1). The new term reflects a better understanding and knowledge of the underlying pathogenic factors (metabolic dysfunction) that drive MAFLD [20]. NAFLD is, by definition, a diagnosis of exclusion based on negative criteria (i.e., alcohol intake quantification) [20,21]. On the other hand, integrating positive criteria (presence of hepatic steatosis) in the MAFLD definition Figure 1. In a bid to raise awareness of the disease, a multidisciplinary group of experts re mended changing the definition and nomenclature of NAFLD to metabolic dysfunction-assoc fatty liver disease (MAFLD). MAFLD is diagnosed in patients with steatosis and at least one o three criteria: obesity/overweight, type 2 diabetes mellitus and any evidence of metabolic dysr lation. NAFLD-non-alcoholic fatty liver disease; MAFLD-metabolic dysfunction-associated liver disease.

Epidemiology and Risk Factors
Overall, the prevalence of NAFLD appears to vary widely depending on the s population (i.e., age, gender, lifestyle, ethnic differences) and the diagnostic methods u [2,[23][24][25]. The increasing worldwide prevalence of obesity, T2DM and metabolic drome may contribute to the high prevalence of NAFLD in the general population [6 Figure 1. In a bid to raise awareness of the disease, a multidisciplinary group of experts recommended changing the definition and nomenclature of NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD is diagnosed in patients with steatosis and at least one of the three criteria: obesity/overweight, type 2 diabetes mellitus and any evidence of metabolic dysregulation. NAFLD-non-alcoholic fatty liver disease; MAFLD-metabolic dysfunction-associated fatty liver disease.

NAFLD Pathogenesis
During the past few decades, significant efforts have been made to clarify the mechanisms underlying NAFLD pathogenesis and progression to NASH. In 1998, Day and James proposed the "two-hit" hypothesis [52]. According to their model of NAFLD pathogenesis, the first hit is represented by intrahepatic triglyceride accumulation triggered mainly by insulin resistance, sedentary lifestyle and central obesity [53,54]. Indeed, insulin resistance is a common cause of increased delivery of free fatty acids and triglycerides to the liver and reduced excretion, eventually leading to intrahepatic fat accumulation [55][56][57][58]. Furthermore, excess carbohydrates represent another significant stimulus for hepatic de novo fatty acid synthesis [55].
According to the multiple-hit hypothesis, a fatty liver is subject to multiple insults that promote hepatic inflammation and fibrosis [19,71]. These multiple hits include a combination of bad nutritional habits, sedentary lifestyle, insulin resistance, epigenetic modifications, alterations in gut microbiota and adipose tissue dysfunction acting altogether on genetically predisposed individuals [19]. Insulin resistance is one of the critical factors in NAFL/NASH pathogenesis that leads to increased hepatic de novo lipogenesis and adipose tissue dysfunction, producing high levels of circulating free fatty acids [72,73]. At the same time, adipose tissue dysfunction may also result in impaired adipokine and inflammatory cytokine production and secretion [73].
In addition, hepatic fat accumulation could lead to lipotoxicity, a severe condition promoting mitochondrial dysfunction with oxidative stress and further aggravation of endoplasmic reticulum (ER) stress [74]. Oxidative stress is defined by a disrupted balance between reactive oxygen and nitrogen species (ROS and RNS, respectively) and the available antioxidant defense mechanisms [75]. Specifically, oxidative stress plays a critical role by acting as a key modulator in NAFLD pathogenesis [76] and inducing hepatocellular injury, liver inflammation and fibrosis [77]. Recent evidence reveals that mitochondrial dysfunction is a significant contributor to oxidative stress, leading to the overproduction of ROS and the consequent elevation in lipid peroxidation products [78]. It is worth mentioning the fact that mitochondria constitute the primary source of ROS in hepatocytes, as ROS are mostly generated from the endoplasmic reticulum and the mitochondrial electron transport chain [79]. ROS also promote the production of inflammatory cytokines via the activation of nuclear factor-κB (NF-κB) and nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing protein 3 (NLRP3) pathways [77]. Furthermore, mitochondrial DNA, which is released in the cytoplasm due to mitochondrial oxidative stress, activates Toll-like receptor 9 (TLR9) on Kupffer cells. Activated Kupffer cells promote the activation of hepatic stellate cells, which, if persistent, lead to liver fibrosis [77].
Dietary factors may also play a central role in gut microbiome alterations, increasing intestinal mucosal permeability and bacterial overgrowth, therefore activating inflammatory pathways [80]. The processes mentioned above lead to the development of a chronic inflammatory state accompanied by hepatocellular death, activation of hepatic stellate cells and fibrogenesis [19]. It is currently supported that the timing and the combination of the multiple parallel hits may help determine whether simple steatosis or NASH will be the initial liver lesion [81].
Meanwhile, the I148M point mutation in the patatin-like phospholipase domaincontaining protein 3 (PNPLA3) gene represents one of the most significant predisposing factors to NAFLD development and advanced liver damage, indicating that there is also a genomic background in NAFLD pathogenesis [82][83][84][85]. In fact, it has been suggested that the accumulation of PNPLA3-148M on the surfaces of lipid droplets (LDs) inhibits triacylglycerol hydrolysis and leads to the impaired mobilization of triglycerides from LDs [86][87][88].

Histological Features
Hepatocellular steatosis (usually macrovesicular) is usually observed in patients with non-alcoholic fatty liver [89]. Other histopathological abnormalities required for the NASH diagnosis include steatosis (macro > micro), lobular inflammation and hepatocellular ballooning (typically seen in the zone 3 steatotic liver cells of the adolescent and adult patients) with or without perisinusoidal fibrosis [89]. Younger children may appear with an alternate pattern characterized by a prominent distribution of steatosis and inflammation in zone 1 [89]. Additionally, Mallory-Denk bodies (eosinophilic cytoplasmic protein aggregates), megamitochondria, hepatocellular glycogenated nuclei, acidophil bodies (apoptotic hepatocytes), and iron deposition represent common histopathological findings in NASH [90]. In most cases, simple steatosis is generally considered to follow a relatively benign clinical course [91]. However, NASH is associated with a more progressive disease course, leading to advanced fibrosis or cirrhosis with all its consequences [92] (Figure 2). In fact, severe NASH may eventually progress to "burnt-out" cirrhosis, for which no characteristic histopathological features remain [15]. Curr. Oncol. 2022, 29 4483 the accumulation of PNPLA3-148M on the surfaces of lipid droplets (LDs) inhibits triacylglycerol hydrolysis and leads to the impaired mobilization of triglycerides from LDs [86][87][88].

Histological Features
Hepatocellular steatosis (usually macrovesicular) is usually observed in patients with non-alcoholic fatty liver [89]. Other histopathological abnormalities required for the NASH diagnosis include steatosis (macro > micro), lobular inflammation and hepatocellular ballooning (typically seen in the zone 3 steatotic liver cells of the adolescent and adult patients) with or without perisinusoidal fibrosis [89]. Younger children may appear with an alternate pattern characterized by a prominent distribution of steatosis and inflammation in zone 1 [89]. Additionally, Mallory-Denk bodies (eosinophilic cytoplasmic protein aggregates), megamitochondria, hepatocellular glycogenated nuclei, acidophil bodies (apoptotic hepatocytes), and iron deposition represent common histopathological findings in NASH [90]. In most cases, simple steatosis is generally considered to follow a relatively benign clinical course [91]. However, NASH is associated with a more progressive disease course, leading to advanced fibrosis or cirrhosis with all its consequences [92] (Figure 2). In fact, severe NASH may eventually progress to "burnt-out" cirrhosis, for which no characteristic histopathological features remain [15]. Non-alcoholic fatty liver: There is fat accumulation within hepatocytes at this stage, a process known as hepatic steatosis. Non-alcoholic steatohepatitis: The accumulation of fat in the hepatocytes is accompanied by liver inflammation and hepatocellular ballooning. Fibrosis: Fibrotic scar tissue starts to form in an inflamed liver. According to the NASH Clinical Research Network (CRN) scoring system, fibrosis staging includes stage 0 (no fibrosis), stage 1A (mild perisinusoidal fibrosis), stage 1B (moderate perisinusoidal fibrosis), stage 1C (portal/periportal fibrosis), stage 2 (perisinusoidal and portal/periportal fibrosis), stage 3 (bridging fibrosis), and stage 4 (cirrhosis). Cirrhosis: End-stage liver disease, in which the formation of fibrotic septa bridges together adjacent portal tracts and central veins. There is an increased risk of hepatocellular carcinoma development. NASH-non-alcoholic steatohepatitis; CRN-Clinical Research Network.

Clinical Features and Diagnostic Workup
Regarding the symptoms, NAFLD is often clinically silent. However, if present, most symptoms are usually non-specific, such as right upper quadrant discomfort or pain (sharp/dull quality), fatigue, abdominal bloating, and sleep disturbances [93]. Mild or moderate hepatomegaly may be present in some NAFLD cases on physical examination.
Most subjects with NASH-related cirrhosis and end-stage liver disease could present with nausea, jaundice, pruritis, ascites, memory impairment and anorexia. Furthermore, Figure 2. Non-alcoholic fatty liver: There is fat accumulation within hepatocytes at this stage, a process known as hepatic steatosis. Non-alcoholic steatohepatitis: The accumulation of fat in the hepatocytes is accompanied by liver inflammation and hepatocellular ballooning. Fibrosis: Fibrotic scar tissue starts to form in an inflamed liver. According to the NASH Clinical Research Network (CRN) scoring system, fibrosis staging includes stage 0 (no fibrosis), stage 1A (mild perisinusoidal fibrosis), stage 1B (moderate perisinusoidal fibrosis), stage 1C (portal/periportal fibrosis), stage 2 (perisinusoidal and portal/periportal fibrosis), stage 3 (bridging fibrosis), and stage 4 (cirrhosis). Cirrhosis: End-stage liver disease, in which the formation of fibrotic septa bridges together adjacent portal tracts and central veins. There is an increased risk of hepatocellular carcinoma development. NASH-non-alcoholic steatohepatitis; CRN-Clinical Research Network.

Clinical Features and Diagnostic Workup
Regarding the symptoms, NAFLD is often clinically silent. However, if present, most symptoms are usually non-specific, such as right upper quadrant discomfort or pain (sharp/dull quality), fatigue, abdominal bloating, and sleep disturbances [93]. Mild or moderate hepatomegaly may be present in some NAFLD cases on physical examination.
According to recent research, several studies support that patients with NAFLD are more prone to develop liver injury and experience more severe symptoms when infected with coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [95,96]. However, other studies report no significant difference in the clinical course between COVID-19 patients with and without fatty liver [96,97].
Indeed, further studies are required to gain a better knowledge of the interactions between COVID-19 and other diseases, such as NAFLD.
Liver biopsy remains the gold standard for diagnosing NAFL/NASH [98]. Indeed, this technique represents an essential tool for histologic evaluation, as it provides information regarding hepatic steatosis, hepatocellular injury, inflammation and fibrosis [98]. Another sensitive tool used for assessing the changes in NAFLD patients during therapeutic trials is the NAFLD activity score (NAS) [99,100]. The steatosis, activity, and fibrosis (SAF) scoring system is a sum of scores used to evaluate the histological severity of NAFLD [98,101,102]. However, none of these histological grading and staging systems for the disease were formed to replace the diagnostic determination of NAFLD [99]. In general, a few significant pathological classifications have been suggested for NAFLD, including NAS, Matteoni's classification, and Brunt's classification [100,103,104]. Liver biopsy is an invasive technique with several drawbacks, such as postprocedural complications, sampling error and high costs [105][106][107]. The experience of the pathologists, inter-observer, and intra-observer variability also represent critical success factors [108][109][110][111]. Therefore, this method should be limited to subjects with diagnostic uncertainty or indeterminate non-invasive staging [112].
Such limitations have raised great interest in developing non-invasive approaches for NAFL/NASH diagnosis. These diagnostic imaging techniques besides ultrasonography (US) include magnetic resonance imaging (MRI) and computed tomography (CT) [113,114]. Additionally, vibration-controlled transient elastography (VCTE) is an essential non-invasive approach for evaluating fibrosis and steatosis in NAFLD patients by measuring liver stiffness [115]. MRI with elastography (MRE) also constitutes a novel technique with high diagnostic accuracy in staging liver fibrosis among NAFLD patients [116][117][118]. Other methods include controlled attenuation parameter (CAP) and acoustic radiation force impulse (ARFI), which are used to assess hepatic steatosis and fibrosis, respectively [112,119].

Treatment
Therapeutic efforts should focus not only on the liver disease itself, but also on its related metabolic disorders. At present, lifestyle modifications, including a healthy diet, weight loss, and increased physical activity, may help improve NAFLD and control blood glucose, pressure, triglycerides, and high-density lipoprotein (HDL) cholesterol levels [143,144]. Indeed, recent studies showed that a healthy diet and exercise could improve liver fat as assessed by US and MRI among NAFLD patients [145,146]. Another important meta-analysis found that patients with a ≥5% weight reduction had significant improvements in hepatic steatosis [147]. In addition, a weight loss of ≥7% was associated with improved histological disease activity (NAS) [147]. Several studies have also shown the positive effects of the combination of low-carbohydrate and Mediterranean diets on body weight and hepatic fat content [148,149]. Meanwhile, bariatric surgery represents another approach for weight reduction and should be considered in selected cases (BMI ≥40 kg/m 2 or a BMI of 35-39.9 kg/m 2 with at least one comorbidity) [150,151]. Bariatric procedures lead to weight loss, reduced chronic inflammation related to obesity, and significant improvements in lipid metabolism and insulin tolerance [152,153].

Association between NAFLD and Extrahepatic Cancers
Over the last decade, it has been shown that there is a substantially increased risk for overall and liver-related mortality in patients with NAFLD [7]. In fact, convincing evidence suggests that NAFLD is a multisystem disease and potentially leads to a significant burden of severe liver-related and extrahepatic complications, including cardiovascular disease, T2DM, and malignancies [8,9] (Figure 3). Current findings reveal increased incidence rates of several extrahepatic malignancies among NAFLD patients [10]. However, the exact mechanisms of how NAFLD could be associated with an increased risk of developing some cancers are not completely understood. A summary of recent studies investigating the association between NAFLD and colorectal neoplasms is presented in Table 1  . overall and liver-related mortality in patients with NAFLD [7]. In fact, convincing evidence suggests that NAFLD is a multisystem disease and potentially leads to a significant burden of severe liver-related and extrahepatic complications, including cardiovascular disease, T2DM, and malignancies [8,9] (Figure 3). Current findings reveal increased incidence rates of several extrahepatic malignancies among NAFLD patients [10]. However, the exact mechanisms of how NAFLD could be associated with an increased risk of developing some cancers are not completely understood. A summary of recent studies investigating the association between NAFLD and colorectal neoplasms is presented in Table 1 [ .

NAFLD and Colorectal Adenomas
Several studies have attempted to investigate the association between NAFLD and colorectal adenomatous polyps, but the reported results remain quite controversial. Nevertheless, most authors demonstrated that NAFLD is significantly associated with an increased risk of developing colorectal adenomas [174,[176][177][178]180,[184][185][186][187][188][189]191,193,195,196,199,200,203,205]. In 2010, a cross-sectional study by Hwang et al. [174] analyzed 2917 participants who underwent a routine colonoscopy based on the evaluation of abdominal ultrasonography, different anthropometric measurements, and other laboratory panels such as liver function tests. The estimated prevalence of NAFLD was 41.5% and 30.2% in the polyp and control groups, respectively. In addition, NAFLD was correlated with a high risk of developing colorectal adenomatous lesions (odds ratio (OR), 1.28; 95% CI, 1.03-1.60; p = 0.029). The authors also showed that the increased risk for NAFLD was primarily observed in patients with multiple adenomas in the polyp group.
Touzin et al. [175] retrospectively analyzed 233 patients who underwent screening colonoscopy, and liver biopsy or abdominal ultrasound. They found no significant difference between the NAFLD and the control groups in the prevalence of colonic adenomas (p = 1.00). However, a low polyp burden was noted in patients with negative ultrasounds for NAFLD. In a cross-sectional study, Wong et al. [176] analyzed 380 community and consecutive patients who underwent a screening colonoscopy. The diagnosis of NAFLD was achieved through proton-magnetic resonance spectroscopy or liver biopsy. The prevalence of colorectal adenomas was higher in NAFLD patients compared with the controls (34.7% vs. 21.5%; p = 0.043). Among the biopsy-proven NAFLD patients, the prevalence of colorectal adenomatous polyps was also higher in the NASH group compared with the NAFL group (51% vs. 25.6%; p = 0.005). At the same time, NASH was found to be significantly associated with the presence of colorectal adenomas (adjusted OR, 4.89; 95% CI, 2.04-11.70; p < 0.001).
Huang et al. [180] conducted a study on 1522 participants who underwent two consecutive colonoscopies. The NAFLD prevalence was higher in the adenoma group, but not in the non-adenoma group subjects (55.6% vs. 38.8%; p < 0.05). The authors revealed that NAFLD was found to be an independent risk factor for developing colorectal adenomas following an initial negative baseline colonoscopy (OR, 1.45; 95% CI, 1.07-1.98; p = 0.016). The risk of developing colorectal adenomatous polyps was increased in NAFLD patients, particularly when other comorbidities were present. In 2015, Bhatt et al. [184] retrospectively studied 591 patients who completed the liver transplant evaluation process. The prevalence of colorectal polyps and adenomas was higher in the NAFLD group compared with the non-NAFLD group (59% vs. 40%; p = 0.003, and 32% vs. 21%; p = 0.04, respectively). The presence of NAFLD appeared to be a significant predictor of finding a colorectal polyp and adenoma (adjusted OR, 2.42; 95% CI, 1.42-4.11; p = 0.001, and adjusted OR, 1.95; 95% CI, 1.09-3.48; p = 0.02, respectively).
In another study by Blackett et al. [199], the researchers also observed that the prevalence of colorectal adenomas was significantly increased in the NAFLD group compared with the control group (40.7% vs. 28.1%; p = 0.01). However, the risk of developing adenomas was not correlated with the severity of NAFLD, particularly with the presence or not of steatohepatitis (adjusted OR, 2.47; 95% CI, 0.67-9.1; p = 0.17). Meanwhile, Yu et al. [201] conducted a cross-sectional study by analyzing 1538 patients with colorectal polyps who underwent abdominal ultrasound and colonoscopy. There was no significant difference in the location and morphology of the polyps between the NAFLD and the control groups (p > 0.05). In fact, NAFLD was correlated with the detection of colorectal polyps, especially among patients with multiple polyps, those with a large size and villous features (p < 0.05).
As mentioned in the above studies, NAFLD patients exhibit an increased risk of developing colorectal adenomas, particularly multiple polyps, most commonly localized in the right and transverse segments of the colon [11,184]. Interestingly, the relationship between NAFLD and colorectal adenomatous polyps emphasizes the necessity of closer surveillance for the early detection of colorectal cancer. However, further evidence is still required to find the ideal target group for the CRC screening of NAFLD patients. It is crucial to evaluate and determine the appropriate age range for CRC screening among NAFLD patients based on results from larger population studies.

NAFLD and Colorectal Cancer
The relationship between NAFLD, CRC and its precursor lesions has been extensively investigated during the past few decades. In general, most guidelines recommend that regular screening should start at age 45 [207]. Obesity, cigarette smoking, and increased alcohol consumption may also be considered significant risk factors for CRC development [208]. In fact, current findings suggest that metabolic syndrome and eventually NAFLD, which is the liver manifestation of metabolic syndrome, may also increase the risk of developing colorectal carcinomas [208]. These associations may guide us to perform screening colonoscopy earlier or more frequently in patients with metabolic syndrome or NAFLD [177,209].
In 2011, a cross-sectional study by Wong et al. [176] analyzed 380 community and consecutive patients undergoing screening colonoscopy. The prevalence of advanced colorectal neoplasms was found to be 18.6% in the NAFLD group and 5.5% in the control group (p = 0.002). Regarding the biopsy-proven NAFLD patients, the prevalence of advanced colorectal neoplasms was 34.7% in the NASH group and 14% in the NAFL group (p = 0.011). In fact, NASH was significantly associated with the development of advanced colorectal neoplasms (OR, 5.34; 95% CI, 1.92-14.84; p = 0.001). Furthermore, Stadlmayr et al. [177] conducted a study on 1211 patients undergoing screening colonoscopy and observed a higher risk of developing CRC in NAFLD patients. The CRC prevalence in men was significantly increased in the NAFLD group than in the control group (1.6% vs. 0.4%; p < 0.001).
In another research, Min et al. [179] retrospectively analyzed 227 patients diagnosed with CRC. They found no significant difference between CRC patients with and without NAFLD regarding the location and differentiation of tumors, carcinoembryonic antigen (CEA), and the total number of synchronous or advanced adenomas. Moreover, the presence of NAFLD did not influence CRC prognosis. Nevertheless, CRC patients with NAFLD were diagnosed earlier compared with CRC patients without NAFLD (p = 0.004). Lin et al. [181] conducted a retrospective and consecutive cohort study on 2315 community participants undergoing a routine colonoscopy. NAFLD appeared to be an independent risk factor for developing colorectal malignant neoplasms (OR, 1.868; 95% CI, 1.360-2.567; p = 0.001).
Another study by You et al. [182] retrospectively analyzed 1314 CRC patients who underwent surgical resection of the tumor. They noted no significant difference in diseasefree survival (DFS) rates between CRC patients with NAFLD and those without NAFLD (p = 0.267). In fact, after the adjustment for different clinicopathologic covariates, NAFLD was revealed to be an independent negative risk factor for overall survival (OS) (hazard ratio, 0.593; 95% CI, 0.442-0.921; p = 0.02), but not for DFS (p = 0.270). In addition, Basyigit et al. [183] studied 127 consecutive patients who underwent colonoscopy and found that CRC prevalence was significantly higher in patients with insulin resistance (p = 0.005). However, the risk of developing CRC was increased in patients with insulin resistance, but without NAFLD (OR, 5.218; 95% CI, 1.538-7.448; p = 0.017).
In a cross-sectional study, Lee et al. [185] analyzed 44,220 individuals participating in a health check-up program and found that the risk of developing colorectal neoplasms increased with worsening fatty liver severity. Currently, Pan et al. [186] also observed a significant association between the presence of CRC and NAFLD (adjusted OR, 2.164; 95% CI, 1.289-3.217; p = 0.005).
Ahn and colleagues [187] found a significant correlation between NAFLD and colorectal neoplasia (adjusted OR, 1.21; 95% CI, 0.99-1.47; p = 0.053). The researchers supported that the risk of developing advanced neoplasms appeared significantly higher for patients with severe liver diseases. Furthermore, Yang et al. [189] studied 1023 patients who had previously undergone surveillance colonoscopy following an index colonoscopy. In fact, at 3 and 5 years after the patients' index colonoscopy, the overall colorectal neoplasm occurrence was 9.1% vs. 5% (NAFLD group vs. non-NAFLD group), and 35.2% vs. 25.3% (NAFLD group vs. non-NAFLD group), respectively (p = 0.01). Even though NAFLD was independently correlated with an increased risk of developing colorectal neoplasms, it was not associated with the presence of advanced colorectal neoplasms (adjusted hazard ratio, 1.07; 95% CI, 0.51-2.26; p = 0.85).
In another study, Kim et al. [190] analyzed 25,947 individuals who underwent colonoscopy as part of a screening program. NAFLD was significantly associated with colorectal carcinomas in men (adjusted hazard ratio, 2.01; 95% CI, 1.10-3.68; p = 0.02), but not in women. Additionally, the severity of NAFLD was not correlated with CRC development. Recently, Chen et al. [192] conducted a cross-sectional study and observed that significant NAFLD was an independent risk factor for CRC-specific mortality in women.
Hamaguchi et al. [194] analyzed 15,926 individuals participating in a health check-up program and found that NAFLD with obesity was independently associated with an increased risk of developing CRC (adjusted hazard ratio, 2.96; 95% CI, 1.44-6.09; p = 0.003). Although Cho et al. [196] noted an association between NAFLD and colorectal adenomas, no significant association was observed between NAFLD and advanced colorectal neoplasms. Nevertheless, NASH was independently associated with an increased risk of developing advanced colorectal neoplasms (adjusted OR, 2.81; 95% CI, 1.01-7.87; p = 0.049).
Kim et al. [204] mentioned a significant association between NAFLD and an increased risk of developing metachronous overall colorectal neoplasia in males (adjusted hazard ratio, 1.17; 95% CI, 1.06-1.29) and females (adjusted hazard ratio, 1.63; 95% CI, 1.27-2.07). Furthermore, an association was also observed between NAFLD and metachronous advanced colorectal neoplasia in women (adjusted hazard ratio, 2.61; 95% CI, 1.27-5.37). Finally, Lee et al. [206] supported that fatty liver disease was correlated with a high risk of developing CRC. The CRC risk was significantly increased in cases with MAFLD, particularly when accompanied by liver fibrosis.
As stated in previous studies, NAFLD patients undergoing a screening colonoscopy were diagnosed with CRC earlier than individuals without NAFLD [176,210]. Although a causal connection between NAFLD and CRC cannot be confirmed, the results of these studies suggest a moderately increased prevalence of CRC among NAFLD patients [210]. Still, further research is required to evaluate the benefits of earlier screening colonoscopy and the role of NAFLD as a predictor for the development of CRC.

Pathophysiological Links between NAFLD, Colorectal Adenomas and Cancer
The association between NAFLD and colorectal neoplasms is the most extensively analyzed in current literature. Nevertheless, the exact pathological mechanisms underlying the link between NAFLD, CRC and colorectal adenomas are not fully understood yet. Considering the bidirectional relationship and strong association between NAFLD and metabolic syndrome [11], several researchers proposed insulin resistance as a significant factor in promoting colorectal neoplasms' development [177]. Indeed, low-grade chronic inflammation [10,174,211,212] in combination with insulin resistance could create a specific microenvironment that would play a key role in cancer initiation and growth via the stimulation of the insulin growth factor-1 (IGF-1) axis by hyperinsulinemia [11]. This pathway may promote tumorigenesis through its anti-apoptotic and proliferative effects [11]. Such effects are also observed through the up-regulation of leptin/AMP-activated protein kinase and resistin/nuclear factor kappa-light-chain-enhancer of activated β cells [NF-κB], the downregulation of adiponectin/caspase or the activation of TNF-α [11]. It should also be kept in mind that adipose tissue dysfunction may represent another possible mechanism leading to cancer development. NAFLD patients appear to have low adiponectin levels and high leptin levels. Overall, adiponectin is considered to have anticarcinogenic effects. It inhibits colorectal cancer cell proliferation via the cyclic AMP-activated protein kinase and induces the caspase-dependent pathway endothelial cell apoptosis [11]. Additionally, adiponectin inhibits TNF-α, which is implicated in the processes of tumor cell proliferation and angiogenesis [11].
On the other hand, leptin has been shown to increase cancer cell invasiveness by activating the mitogen-activated protein kinase (MAPK) pathway in human colon cancer cells [11,213,214]. The state of chronic low-grade inflammation related to insulin resistance contributes to the build-up of a microenvironment favorable to the development of neoplasms. High levels of proinflammatory cytokines increase cellular proliferation and trigger the inhibition of apoptosis and angiogenesis [10,174]. Although animal studies have supported a causal relationship between alterations in gut microbiota and NAFLD, few human studies have started to describe the presence of such alterations among NAFLD patients [215]. Recently, it has been suggested that microRNAs (miR) (particularly miR-21 and miR-451 acted as an oncogene and a tumor suppressor gene, respectively) may play an essential role during NAFLD and CRC development [216,217]. However, further studies are required to establish a causal relationship between microRNAs and the development of NAFLD and CRC.

NAFLD and Other Extrahepatic Cancers
During the past decades, several researchers examined the influence of obesity, particularly abdominal fatness, on the risk of developing various extrahepatic cancers. Overall, abdominal obesity is strongly associated with metabolic syndrome. Consequently, the hepatic manifestation of metabolic syndrome, NAFLD, and its correlation with cancer risk is now considered a topic of great interest and ongoing research. Whether NAFLD could lead to an increased risk of developing cancer is still a subject of heated debate. However, more recent studies focused on exploring the role of NAFLD in extrahepatic malignancies to identify if NAFLD could act as a driving force in cancer development (Figure 4).
Esophageal cancer, the 8th most common malignancy globally, is considered to be strongly associated with obesity [11]. In fact, obesity represents a significant risk factor for developing esophageal cancer by increasing the risk up to approximately four-fold compared with lean individuals [11,218]. Several studies support that central adiposity, independent of BMI, is associated with the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), eventually contributing to the progression from inflammation to metaplasia (BE) and neoplasia (EAC) [219]. According to other researchers, their results showed a significant dose-dependent correlation between BMI and the risk of developing EAC [218]. subjects with higher waist circumferences, independent of BMI, were found to be at a 1.5-2.8-fold increased risk of developing BE among both males and females [220]. Similarly, other studies also suggest that visceral abdominal fat could represent a significant risk factor for the development of BE [221].
Despite the potential association between obesity and esophageal cancer, visceral obesity is also closely related to metabolic dysregulation and NAFLD [222,223]. Considering these findings, more researchers focused on investigating the relationship between NAFLD and esophageal cancer. In 2017, Kim et al. [190] observed that a high NAFLD fibrosis score and FIB-4 score were strongly associated with the development of several cancers, including cancer of the esophagus. However, there was no significant difference in the incidence of esophageal cancer between patients with and without NAFLD. Contrary to their expectations, Allen et al. [197] also observed that obese or NAFLD patients did not exhibit an increased risk of developing esophageal cancer. Recently, Lee et al. [198] noted that NAFLD (FLI score ≥ 60) was significantly correlated with a high risk of developing esophageal cancer (hazard ratio, 2.10; 95% CI, 1.88-2.35) and all-cause mortality in esophageal cancer patients (hazard ratio, 1.46; 95% CI, 1.28-1.67).

NAFLD and Other Extrahepatic Cancers
During the past decades, several researchers examined the influence of obesity, particularly abdominal fatness, on the risk of developing various extrahepatic cancers. Overall, abdominal obesity is strongly associated with metabolic syndrome. Consequently, the hepatic manifestation of metabolic syndrome, NAFLD, and its correlation with cancer risk is now considered a topic of great interest and ongoing research. Whether NAFLD could lead to an increased risk of developing cancer is still a subject of heated debate. However, more recent studies focused on exploring the role of NAFLD in extrahepatic malignancies to identify if NAFLD could act as a driving force in cancer development (Figure 4). Esophageal cancer, the 8th most common malignancy globally, is considered to be strongly associated with obesity [11]. In fact, obesity represents a significant risk factor for developing esophageal cancer by increasing the risk up to approximately four-fold compared with lean individuals [11,218]. Several studies support that central adiposity, independent of BMI, is associated with the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), eventually contributing to the progression from inflammation to metaplasia (BE) and neoplasia (EAC) [219]. According to other researchers, their results showed a significant dose-dependent correlation between BMI and the risk of developing EAC [218]. Subjects with higher waist circumferences, independent of BMI, were found to be at a 1.5-2.8-fold increased risk of developing BE among both males and females [220]. Similarly, other studies also suggest that visceral abdominal fat could represent a significant risk factor for the development of BE [221]. In a current study, Hamaguchi et al. [194] found that NAFLD with obesity was a significant risk factor for developing gastric cancer (adjusted hazard ratio, 3.58; 95% CI, 1.73-7.38; p = 0.001). Furthermore, Allen et al. [197] revealed that the highest risk of malignancy among NAFLD patients was observed in liver cancer, followed by uterine and gastric cancer (incidence rate ratio, 2.3; 95% CI, 1.3-4.1). In agreement with these results, Lee et al. [198] showed that NAFLD was associated with an increased risk of developing gastric cancer (hazard ratio, 1.18; 95% CI, 1.14-1.22) and all-cause mortality in gastric cancer patients (hazard ratio, 1.26; 95% CI, 1.18-1.34). Hence, another critical issue that must be addressed is whether NAFLD patients should be encouraged to undergo screening for gastric cancer.
Some researchers investigated the relationship between BMI, abdominal fatness, and pancreatic cancer risk [228]. Indeed, there was a significant association between BMI and waist circumference with the risk of developing pancreatic cancer [228]. In addition, when the analyses were restricted to nonsmokers, there was an increased risk of pancreatic cancer development even among individuals within the normal BMI range [228]. Another study revealed a significant correlation between metabolic syndrome and pancreatic cancer (relative risk, 1.58; p < 0.0001). This association was stronger in females than in males (p = 0.01) [229].
In contrast to Kim et al. [190], who did not observe any difference in the incidence of pancreatic cancer between subjects with and without NAFLD, Chang et al. [230] revealed a positive correlation between NAFLD and pancreatic cancer risk. In fact, pancreatic cancer patients with NAFLD had poorer overall survival than patients without NAFLD, suggesting that NAFLD could be used as a prognostic factor for pancreatic cancer. Allen et al. [197] also observed an increased risk of developing pancreatic cancer among NAFLD patients (incidence rate ratio, 2.0; 95% CI, 1.2-3.3), particularly at a younger age (incidence rate ratio, 0.85; 95% CI, 0.74-0.98).
In 2017, Lee et al. [231] supported that the NAFLD prevalence among breast cancer patients did not differ from that of the general population. Meanwhile, contrary to Lee et al., current studies have shown a correlation between NAFLD and breast cancer. At first, Nseir et al. [232] found that the NAFLD prevalence was higher in females with breast cancer compared with the control group (45.2% vs. 16.4%, p = 0.002). Multivariate analysis revealed a significant association between NAFLD and breast cancer (OR, 2.82; 95% CI, 1.2-5.5; p = 0.016). Then, Kim et al. [190] also noted a strong association between NAFLD and breast cancer in females (hazard ratio, 1.92; 95% CI, 1.15-3.20; p = 0.01). In another research, Kwak et al. [233] observed the correlation between NAFLD and breast cancer in the nonobese subjects (OR, 3.04; 95% CI, 1.37-4.32; p = 0.002), but not in the obese subjects (p = 0.163).
The association between NAFLD and other extrahepatic malignancies is less frequently reported and proven. A meta-analysis conducted by Maclnnis et al. [237] revealed a weak association between NAFLD and prostate cancer risk (mainly concerning advanced stage tumors). At the same time, Arase et al. [238] noted that the third most commonly found malignancy among NAFLD patients was prostate cancer (12.6%). In another research, Choi et al. [239] suggested that the presence of NAFLD was considered to be protective against prostate cancer biochemical recurrence after radical prostatectomy. According to Allen et al. [197], the highest risk of developing malignancy among NAFLD patients was observed in liver and uterine cancer (incidence rate ratio, 2.3; 95% CI, 1.4-4.1). On the other hand, Huber et al. [236] found that NAFLD was associated with an increased risk of developing skin cancer (irrespectively of sex) and genital cancer in males. Simon et al. [240] mentioned a correlation between NAFLD and a modest increase in kidney/bladder cancer and melanoma. Some authors also showed that high levels of a metabolic risk score composed of five features (blood pressure, BMI, total cholesterol, triglyceride and glucose levels) were associated with renal cell cancer development [241]. Meanwhile, other authors [242] observed an association between NAFLD, obesity and pulmonary adenocarcinoma, particularly among nonsmoking females.

Conclusions
Overall, NAFLD represents a major cause of liver dysfunction and chronic liver disease globally. It is a silent liver disease, mostly without causing any symptoms. However, as a multisystem disease, NAFLD may lead to severe liver-related and extrahepatic complications, including malignancies. Several researchers have pointed out the possible links between NAFLD and gastrointestinal tract malignancies. Indeed, the association of NAFLD with colorectal adenomas and cancer has been thoroughly investigated during the past decades. Nevertheless, further studies are required to gain a better knowledge and understanding of the mechanisms underlying the association between NAFLD and cancer risk. The presence of NAFLD might act as a prognostic factor for developing extrahepatic cancer.
As a result, early NAFLD diagnosis could help prevent the progression of the disease and