colorectal cancer ( crc ) remains as one of the commonest cancers worldwide , with a million new cases diagnosed each year . in the uk it is also the second leading cause of cancer deaths worldwide [ 3 , 4 ] . established risk factors include increased age , black race , smoking , and low fibre diet . suggestions from data now point at obesity , insulin resistance , and the metabolic syndrome also as potential risk factors . it includes at least three of the following : increased waist circumference , hypertriglyceridaemia , low high - density lipoprotein ( hdl ) , hypertension , and hyperglycaemia . it is also stipulated that one of its hepatic manifestations , the nonalcoholic fatty liver disease ( nafld ) , may be an independent risk factor for developing colorectal cancer [ 6 , 7 ] . this paper highlights the association between colorectal cancer and nafld , the metabolic syndrome , diabetes , and hyperlipidaemia . it is an umbrella term describing a spectrum of diseases associated with excessive fat accumulation in the liver ( steatosis ) , in the absence of excessive alcohol consumption . the spectrum of the condition ranges from simple steatosis , to steatohepatitis ( nash ) , through to advanced fibrosis / cirrhosis and even hepatocellular carcinoma . the characteristic histological features of nafld are indistinguishable from those of alcohol - induced fatty liver disease but are also found in people who consume minimal alcohol . it is regarded as the commonest cause of deranged liver enzymes in the usa and is associated with type 2 diabetes , obesity , and hyperlipidaemia [ 8 , 9 ] . it is defined as the accumulation of liver fat by > 5% per liver weight , in the presence of < 10  g of daily alcohol consumption [ 1012 ] . the estimated prevalence of nafld in usa is thought to be around 34% , and interestingly 90% of these cases are attributed largely to obesity and diabetes . the dallas heart study which was based on a large , multiethnic probability - based population reported that the prevalence of nafld is around 33.6% . additionally , the use of ultrasound in the dionysos nutrition and liver disease study in italy showed that the prevalence of steatosis was increased in heavy drinkers and obese persons . this study concluded that steatosis is frequently encountered in healthy people and is usually present in the obese who drink more than 60  g of alcohol per day . steatosis is more strongly associated with obesity than with heavy drinking , suggesting a greater role of obesity than alcohol consumption in the accumulation of fat in the liver . nafld is associated with morbid obesity , type 2 diabetes , and hyperlipidaemia ; however , excess alcohol intake is still the main cause of fatty liver disease . the increase in prevalence of the epidemic of type 2 diabetes and obesity is likely to increase the prevalence of nafld in the near future with serious financial implications for health care providers [ 16 , 17 ] . a failure in diagnosing nafld may lead to an insidious progression of the condition which may result in cirrhosis , portal hypertension , and liver - related death in early adulthood . importantly , nafld is associated with an increased risk of all - cause death and predicts future cvd events , independently of age , sex , ldl cholesterol , smoking , and the cluster of features of the metabolic syndrome . nafld is regarded as the hepatic manifestation of the metabolic syndrome , an entity associated with colorectal carcinogenesis . the reported prevalence of obesity with nafld varies between 30% and 100% , whereas the prevalence of nafld with type 2 diabetes varies between 10% and 75% . the lack of sensitive and specific biochemical markers have attracted a lot research interest , as it is predicted that mass screening for significant liver injury in patients with nafld may play an important role in the years to come because of the increase in obesity and diabetes . one of these studies was carried out by adams et al . , who looked at the impact of nafld on mortality among 337 patients with type 2 diabetes followed for 9 years . among these , 116 were diagnosed with nafld 0.9  4.6 years after diabetes was diagnosed . those found to have developed nafld were younger and more likely to be female and obese . in multivariate analysis , they showed that beside increased risk of ihd and diabetes , nafld is associated with an increased risk of dying from malignancy ( hr 2.3 ; 95% ci 0.9 , 5.9 ; p = 0.09 ) . in context , a diagnosis of nafld should be taken seriously , and steps to exclude malignancy should be taken . hwang et al . presented the first evidence that demonstrated an association between nafld and an increased rate of colorectal adenomatous polyps . in their study , a population of 2917 participants were investigated via colonoscopy , abdominal ultrasonography , and liver tests . the prevalence of nafld was 41.5% in the adenomatous polyp group versus 30.2% in the control group providing the first evidence that an association may exist . by multiple logistic regression analysis , nafld was found to be associated with an increased risk of colorectal adenomatous polyps ( odds ratio , 1.28 ; 95% confidence interval , 1.031.60 ) . interestingly , an increased risk for nafld was evident in patients with a greater number of adenomatous polyps . if left untreated , these polyps develop into colorectal cancer ( adenoma - carcinoma sequence ) . furthermore , wong et al . showed that in a cross - sectional study of 4070 year olds ( n = 199 ) , nafld patients ( n = 199 ) had a higher prevalence of colorectal adenomas ( 34.7% versus 21.5% ; p = 0.043 ) and advanced neoplasms ( 18.6% versus 5.5% ; p = 0.002 ) . among patients with biopsy - proven nafld , patients with nash ( n = 49 ) had a higher prevalence of adenomas ( 51.0% versus 25.6% ; p = 0.005 ) and advanced neoplasms ( 34.7% versus 14.0% ; p = 0.011 ) than those with simple steatosis ( n = 86 ) . after adjusting for demographic and metabolic factors , nash remained associated with adenomas ( adjusted or 4.89 , 95% ci 2.04 to 11.70 ) and advanced neoplasms ( or 5.34 , 95% ci 1.92 to 14.84 ) . this may suggest that nash is associated with higher risk of colorectal adenoma , demonstrating a correlation between histological severity with colorectal cancer , adding further fuel to the relationship between nafld and colorectal cancer , and suggesting the potential benefit of colorectal cancer screening in this group . in a large retrospective cohort study of korean women , lee et al . found a significant relationship between nafld and colorectal neoplasia . the study included data from 5517 women , aged 3580 years , who underwent life insurance health examination between 2002 and 2006 at their institution . , 65 women were found to have adenomatous polyps , and 15 women were found to have colorectal cancer . furthermore , the risk of adenomatous polyps in patients with nafld was twice that of patients without nafld , and adjusted rrs ( 95% ci ) for adenomatous polyps by age , low hdl - cholesterol , and nafld were 1.12 ( 95% 1.091.15 ) , 2.56 ( 95% ci 1.534.28 ) , and 1.94 ( 95% ci 1.113.40 ) . there was a threefold increase in the risk of colorectal cancer in patients with nafld compared to the healthy subjects , and adjusted rrs ( 95% ci ) for colorectal cancer by age and nafld were 1.23 ( 95% ci 1.171.29 ) and 3.08 ( 95% ci 1.029.34 ) . however , the presence of nafld had no influence on the prognosis of crc and in particular with disease recurrence during followup . in another study , 1200 patients ( 603 males and 608 females ) underwent screening colonoscopy . . showed that the patients with nafld had significantly more colorectal adenomas and early colorectal cancers compared to those without nafld . nafld was diagnosed in 367 ( 60.8% ) in the male group and in 265 ( 43.5% ) in the female group . the rate of colorectal adenoma was significantly higher in patients with nafld . in the male group with nafld , the rate of adenomas was 243/367 versus 107/236 , p = 0.010 . in the female group with nafld , the rate of adenomas was 96/265 versus 78/343 in women without nafld , p = 0.014 . however , significantly more colorectal cancers were observed in the males with nafld , 6/367 versus 1/236 , p < 0.001 , and not in the female group with nafld . multivariate regression analyses demonstrated an independent association of colorectal adenomas with nafld after adjustment of age , sex , body mass index ( bmi ) , and glucose intolerance ( or 1.47 ; 95% ci 1.0792.003 , p = 0.015 ) . overall , the males with nafld had more tubular adenomas , rectal adenomas , and more cancers , whilst the females with nafld were shown to have more tubular adenomas and adenomas of the proximal colon . in contrast , touzin et al . have failed to demonstrate an increase in incidence of colorectal adenomas in patients with nafld compared to those without . in this retrospective observational study of smaller number of patients of 233 who underwent screening colonoscopy , they compared patients with sonographic imaging and biopsy - proven simple steatosis ( n = 65 ) , or non - alcoholic steatohepatitis ( nash ) , ( n = 29 ) , to a control group of 139 patients without nalfd on sonographic imaging . the prevalence of adenomas was 35/139 ( 25.1% ) in the control group compared to 23/94 ( 24.4% ) in patients with nafld ,  p = 1.00 . after adjustment of the known cofounder to include race , bmi , and family history , no significant difference was found in the two groups , p = 0.33 . interestingly , the mean number of adenomas was significantly higher in patients with nafld compared to the control group , p = 0.016 . compared to the previous study the patients in this group were younger , 55 years compared to 65 years in the study by stadlmayr et al . . the proposed mechanism for how nafld influences carcinogenesis is not completely understood ( figure 2 ) . it is known , however , that nafld represents a condition of profound insulin resistance and a proinflammatory state . insulin and insulin - like growth factors may promote the development of colorectal neoplasm through their proliferative and antiapoptotic effects . patients with nafld have reduced expression of adiponectin , an adipokine with anti - inflammatory effects [ 25 , 26 ] . this is also the case in the obese , diabetic , and those with insulin resistance . decreased levels of adiponectin lead to increased insulin levels due to marked insulin resistance and in turn increased insulin growth factor-1 ( igf-1 ) . insulin binds to igf-1 receptors and plays an important role in cell proliferation , apoptosis , and increased production of vascular endothelial growth factor , an angiogenic factor that supports cancer growth . the new anticancer antibody bevacizumab is human monoclonal antibody that inhibits vascular endothelial growth factor a and is licensed for use in metastatic colorectal cancer . studies in humans have shown an association between hypoadiponectinemia and an increased risk of colorectal adenomas . adiponectin inhibits colorectal cancer cell growth in vitro , and mice with hypoadiponectinaemia had increased risk of colonic polyps when exposed to a high - fat diet . mediators derived mainly from adipose tissue such as adiponectin or leptin could be critically involved in such processes , and , therefore , these so - called adipocytokines might reflect attractive candidates linking obesity - related disorders with tumour development both intra- and extrahepatically . it is well established that those with nafld , especially nash , have significantly lower levels of serum adiponectin compared to healthy controls .   indeed , an association of obesity and hypoadiponectinaemia with colorectal adenomas and cancer has been shown in men . another study demonstrated an inverse correlation of total and high molecular weight adiponectin serum levels with development of colorectal adenomas . it demonstrates anticarcinogenic effects in vitro through the inhibition of colon cancer cell growth via the stimulation of amp - activated protein kinase activity . this has been further supported by mice tumour model which also demonstrated that adiponectin significantly stopped the growth of the primary tumour in a caspase - dependent manner resulting in endothelial cell apoptosis . according to ferroni et al . and rose et al . , adiponectin also directly inhibits tumour necrosis factor alpha ( tnf- ) , a mediator known to play a role in tumour cell proliferation and angiogenesis [ 34 , 35 ] . low adiponectin levels were shown to be inversely related to colonic tumour stage and independently predicted cancer recurrence . inflammatory cytokines may also play a role in colorectal cancer and are related to the metabolic syndrome via adipocyte secretion of various cytokines , including tnf- [ 37 , 38 ] . through hypoxia , adipocytes would then secrete cytokines which stimulate angiogenesis into the adipose cells , and these cytokines in turn also promote insulin resistance and increase circulating triglycerides . this pro - inflammatory state influences growth , apoptosis and tumour - cell proliferation in many cancers [ 3941 ] . many studies have also investigated the effects of leptin , another adipocytokine dysregulated in obesity and nafld , in experimental cellular and animal models . these suggest that leptin can induce carcinogenesis , whilst adiponectin seems to decrease cell proliferation . it is purported that through its interference with leptin , adiponectin may have an anti - carcinogenic effect , while leptin would exert a carcinogenic state under low adiponectin level . the relationship between nafld and colonic carcinogenesis emphasises the importance of a healthy lifestyle to prevent and treat the metabolic syndrome and its hepatic manifestation . since nafld and colorectal neoplasms postulated that nafld patients have an increased risk of colorectal neoplasms and should be a target group for screening . colorectal cancer is a leading cause of cancer - related deaths worldwide , and screening would reduce the incidence and mortality of colorectal cancer . they strongly advocated screening in nash patients as proximal colonic lesions are common in these patients , and colonoscopy would be considered as the preferred screening method . furthermore , patients with metabolic syndrome are more likely to develop cancer in the proximal colon and may only be detected by full colonoscopy [ 21 , 43 ] . it has recently been shown that in average - risk individuals , 4049 years of age , men with abdominal obesity or metabolic syndrome might benefit from screening colonoscopy starting at 45 years of age to detect colonic neoplasms . the presence of nash might be an important prognostic factor in liver disease and additionally in extra hepatic prognosis , that is , cancer development . the metabolic syndrome and visceral obesity have an increasing prevalence and incidence in the general population , with an estimated 24.6% and 30.9% in europe . several clinical features of the metabolic syndrome , including obesity , dyslipidaemia , and impaired glucose tolerance , have been linked to an increased risk for colorectal cancer in several recent epidemiological studies . the mechanism by how it does this is mainly related to abdominal obesity and insulin resistance , with studies demonstrating that carcinogenesis is linked to hyperinsulinaemia , increased c - peptide , increased bmi , high levels of igf-1 , low levels of insulin growth factor binding protein-3 , high leptin levels , and low adiponectin levels . in a nested control study that included 1093 individuals , among individual components of the metabolic syndrome , abdominal obesity ( rr = 1.51 ; 95% ci : 1.161.96 ) was associated with colon cancer , whereas abnormal glucose metabolism was associated with both colon ( rr = 2.05 ; 95% ci : 1.572.68 ) and rectal cancers ( rr = 2.07 ; 95% ci : 1.452.96 ) . in another study in the usa of 900,000 individuals who had undergone 16-year follow up , they found 57,145 cancer - related deaths . they found that for all cancers , there was a trend of increasing death rate with increased bmi , and the relative risk of colorectal cancer showed a dose response to an increasing bmi as well . a further study by ahmed et al . of 14,109 individuals identified 194 colorectal cancers and found that after adjusting for age and gender , they found that baseline metabolic syndrome ( > 3 components versus 0 components ) had a positive association with colorectal cancer incidence . after multivariate adjustment , they found a dose response association between colorectal cancer incidence and the number of metabolic syndrome components . this was reenforced in a study which suggested that the effects of the individual components of the metabolic syndrome may be additive , as they demonstrated that the relative risk of death from colorectal cancer was increased in cluster analysis compared to glucose level alone . out of the individual components , only glucose level  was associated with an increased risk of colorectal cancer death , and only if both genders were combined . the relationship between individual components of metabolic syndrome and the risk of colorectal cancer has been analysed in other studies . one such study was carried out by colangelo et al .   who found that there was a 35% increased risk of colorectal cancer associated with high blood pressure and also found that clustering of features of the metabolic syndrome significantly increased the risk of associated colorectal cancer . furthermore , kabat et al . showed that an increase in glucose level and systolic blood pressure is also associated with high risk of colon cancer . there is increasing evidence that abnormal glucose metabolism is associated with an increased risk of colorectal cancer [ 51 , 52 ] . there is an extensive body of research examining the relationship between diabetes and colorectal cancer , and findings have so far varied , with relative risks of colorectal cancer ranging from 1.2 to 2.8 in prospective cohort studies . studies have positively correlated colorectal cancer with c - peptide levels ( insulin - release marker ) , 2-hour postchallenge insulin and glucose concentrations , and haemoglobin a1c levels . in one study , greater median fasting insulin values ( 14400  iu / ml ) were associated with a 1.6-fold increased risk of colorectal cancer compared to values of 313  iu / ml . in another study , there was also a weak positive association between incidental colorectal cancer and fasting insulin level . khaw et al . examined the relationship between known diabetes and glycated haemoglobin ( hba1c ) concentrations measured in 9,605 men and women and subsequent incident colorectal cancer after 6 years follow up in the european prospective investigation into cancer - norfolk study [ 51 , 52 , 54 ] . their main finding is that the risk of colorectal cancer increased after hba1c concentrations above 7% . additionally , they found that an absolute increase of 1% in hba1c was associated with a 33% increase in risk of colorectal cancer . interestingly , when both hba1c and known diabetes were included in the same multivariate model , glycated hba1c remained a significant risk predictor , but the effect of diabetes status was no longer significant . they suggested that the increased risk of colorectal cancer in diabetics was mediated via the increased hba1c levels . this relationship between colorectal cancer and hba1c was also present in the clue ii cohort [ 52 , 54 ] . several studies have reported stronger associations between impaired glucose tolerance and cancer than diabetes with cancer . saydah et al . reported a significant risk of colorectal cancer mortality with impaired glucose tolerance , but not diabetes ( rr 1.87 versus 1.13 ) . overall findings of diabetes association with colorectal cancer have not been entirely consistent . some have suggested that this may be due to the alternating course of diabetes , with insulin resistance initially associated with hyperinsulinaemia , and in latter stages it leads to hypoinsulinaemia secondary to b - cell failure . this variability in severity and duration may explain the inconsistencies observed in studies associating diabetes with cancer . a metaanalysis by mulholland et al . looked at the association between diets with a high glycaemic index ( gi ) and high glycaemic load ( gl ) , with the risk of digestive tract cancers . they reported that pooled cohort studies failed to demonstrate an association between colorectal cancer risk and high glycaemic intake . they did report , however , that two studies observed positive associations between gi and gl intake with colorectal cancer risk in those with an above - normal bmi . the impact of bmi has been shown to be inconsistent , with other studies failing to show such an association . insulin has been shown to affect the growth of both normal and neoplastic epithelial cells and to have the capability of promoting mitosis in vitro , directly or indirectly via igf-1 . it has been proposed that insulin and insulin - like growth factors may be involved in colon carcinogenesis [ 45 , 48 ] . insulin acts as a growth factor , and insulin receptors are present in normal and malignant colorectal cells . hyperinsulinaemia may also affect the development of colorectal cancer , indirectly by downregulating insulin - like growth factor binding proteins ( igfbp-1 , 2 , 3 ) , thus enhancing igf-1 bioavailability . igf-1 which is an important mitogen for progression through the cell cycle having autocrine , paracrine , and endocrine actions on cell proliferation and apoptosis , leads to increased cell proliferation , inhibition of apoptosis and promotion of tumour growth . igf-1 also increases the production of vascular endothelial growth factor ( vegf ) , an angiogenic factor that may support cancer growth . the association of igf-1 and igfbp-3 levels with their effects on increased risk of colorectal adenoma / cancer initially came into knowledge through acromegalics , which have chronically increased growth hormone ( gh ) levels . excess gh leads to hepatic and peripheral insulin resistance leading to excess insulin , causing igf-1 hypersecretion and low igfbp-3 levels . giovannucci et al . studied the relationships between igf-1 and igfbp-3 levels and colorectal cancer in a study of 32,826 women . they showed that those with higher levels of igf-1 were at increased risk of intermediate / late - stage colorectal neoplastic adenoma and cancer . the women with higher levels of igfbp-3 were at lower risk of intermediate / late - stage colorectal adenoma and cancer , indicating opposing effects of igf-1 and igfbp-3 to colorectal cancer . hence , loss of igfbp-3 could contribute to the development of colorectal adenomas that retain wild - type p53 function through the suppression of p53-dependent apoptotic signals , promoting survival of abnormal cells and tumourigenesis . these studies suggest that igfbp-3 may have an important role in the regulation of differentiation and apoptosis in human colonic epithelium . a high body mass index ( bmi ) has been shown to be associated with an increased mortality not only from atheromatous disease , but also from some cancers . there is a plethora of evidence to suggest an increased risk of colorectal cancer in the obese , and obesity has been included as an important risk factor in the recent guidelines from the american college of gastroenterology for screening colorectal cancer . it has a direct and independent relationship with colorectal cancer , though the association seems to be weaker than previously reported . a study suggests that obesity and weight gain may induce early colorectal carcinogenesis in women especially those arising in the distal colon . obesity is the usual cause for the development of nafld , an entity that has been linked to both extrahepatic and colorectal cancers .   in a study of 600 patients with a median age of 56 , 185 patients were classified as obese , and of these there was a 44.3% prevalence of  any  adenomas and a 13% prevalence for advanced neoplasia after undergoing colonoscopy . after multivariate analysis , obesity ( bmi  30 ) was significantly associated with an increased risk of advanced neoplasia ( odds ratio ( or ) = 3.83 ; 95% ci 1.947.55 ) . furthermore , the increase in waist circumference and bmi was associated with an increase in risk of colorectal cancer . wang et al . showed that in both men and women , waist circumference was associated with increased colorectal incidence . high bmi levels were also associated with an increased risk . however , after adjustment for bmi , waist circumference remained associated with a nonstatistically significant increase in colorectal cancer incidence in both genders . the conclusion was that increased incidence of colorectal cancer due to an increased waist circumference may be partially independent of bmi . for colorectal cancer , the rr of death varied from 1.34 ( 95% ci : 0.941.34 ) , for a bmi of 2529.9 , to 1.90 ( 95% ci : 1.462.47 ) and 4.52 ( 95% ci : 2.946.94 ) , for a bmi between 30.034.9 and 35.039.9 , respectively . the relationship between bmi and colon cancer was also studied in the epic study , which was based on 984 cases of colon cancer . in a retrospective study of 7566 subjects by moore et al . they showed a twofold increased risk of colorectal cancer for waist circumference of > 99  cm in women and > 101  cm in men , and this risk increased linearly with increased waist - circumference . another suggestion is that visceral adipose tissue rather than whole body adipose tissue correlates better with the risk of colorectal adenoma . furthermore , in a large prospective study , high circulating triglycerides were associated with a nonsignificant twofold elevation in risk of colorectal cancer in men , but no clear association was observed in women . in addition , hypertriglyceridemia and hyperglycaemia were associated with colorectal carcinoma [ 68 , 69 ] importantly , meta - analysis of 18 studies involving more than 1.5 million patients showed that statins treatment is not associated with significant decrease in risk of colorectal cancer . therefore , we recommend that further research is urgently needed to establish the role of hyperlipidaemia as risk factor for colorectal cancer . additional prospective studies are needed to better define a true association between nafld and adenomatous colon polyps . therefore , it is good clinical practice to exclude the presence of colon cancer in individuals with long - standing nafld . furthermore , several studies suggest that metabolic syndrome and its components are associated with increased risk for colonic neoplasm . this relationship has an important impact on society and further emphasizes the importance of a healthy lifestyle to prevent and treat metabolic syndrome and its hepatic manifestation , nafld . it is not yet clear what an impact of the treatment of nafld on modulation of the risk of colon cancer is .
nonalcoholic fatty liver disease ( nafld ) is closely related to insulin resistance , metabolic syndrome , obesity , type 2 diabetes , and dyslipidaemia . obesity and metabolic syndrome are associated with an increased cancer risk , and recent evidence demonstrated an association between nafld and colorectal cancer ( crc ) . 
 the mechanism of how nafld can be associated with increased risk of crc is not fully understood ; however , nafld represents a condition of profound insulin resistance and a proinflammatory state . 
 insulin and insulin - like growth factors may promote the development of crc through their proliferative and antiapoptotic effects . 
 patients with nafld have reduced expression of adiponectin , an adipokine with anti - inflammatory effects . 
 importantly , hypoadiponectinemia is associated with an increased risk of crc . decreased levels of adiponectin lead to increased insulin levels due to marked insulin resistance and in turn increased insulin growth factor-1 ( igf-1 ) . 
 insulin binds to igf-1 receptors and plays an important role in cell proliferation , apoptosis , and increased production of vascular endothelial growth factor , an angiogenic factor that supports cancer growth . 
 further studies are needed to establish ( i ) the pathophysiology of nafld with colorectal cancer , ( ii ) the benefit of early screening of crc in nafld patients , and ( iii ) the impact of treatment of nafld in the modulation of the risk of colorectal cancer .