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This page is the ScienceSource HTML version of the scholarly article described at https://www.wikidata.org/wiki/Q28073381. Its title is Obesity-Related Digestive Diseases and Their Pathophysiology and the publication date was 2017-05-15. The initial author is Su Youn Nam.

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Journal Information

Title: Gut and Liver

Obesity-Related Digestive Diseases and Their Pathophysiology

  • Su Youn Nam

Publication date (ppub): 5/2017

Publication date (epub): 11/2016


Obesity is a growing medical and public health problem worldwide. Many digestive diseases are related to obesity. In this article, the current state of our knowledge of obesity-related digestive diseases, their pathogenesis, and the medical and metabolic consequences of weight reduction are discussed. Obesity-related digestive diseases include gastroesophageal reflux disease, Barrett’s esophagus, esophageal cancer, colon polyp and cancer, nonalcoholic fatty liver disease, hepatitis C-related disease, hepatocellular carcinoma, gallstone, cholangiocarcinoma, and pancreatic cancer. Although obesity-related esophageal diseases are associated with altered mechanical and humoral factors, other obesity-related digestive diseases seem to be associated with obesity-induced altered circulating levels of adipocytokines and insulin resistance. The relationship between functional gastrointestinal disease and obesity has been debated. This review provides a comprehensive evaluation of the obesity-related digestive diseases, including pathophysiology, obesity-related risk, and medical and metabolic effects of weight reduction in obese subjects.



The prevalence of global obesity among both women and men increased from 1980 to 2008 (Fig. 1).[1] With a new appreciation for obesity as a disease and well-being in mind, the concerns of obesity and obesity-related disease have been rapidly increased. The health implications by obesity include a wide spectrum of benign digestive diseases such as gastroesophageal reflux disease (GERD), Barrett’s esophagus (BE), erosive esophagitis, nonalcoholic fatty liver disease (NAFLD), gallstones, and pancreatitis and digestive organ cancers such as cholangiocarcinoma, hepatocellular carcinoma (HCC), pancreatic cancer, colorectal cancer (CRC), and esophageal cancer (Fig. 2).[2][5] Obesity and related comorbid conditions may also increase risk for common adverse treatment effects in cancer patient.[6]

Both mechanical effect and humoral factors by obesity seem to effect on development of esophageal diseases, whereas pathophysiology of other digestive disorders seems to be related with obesity induced proinflammatory and inflammatory cytokines. The relationship of functional gastrointestinal disease with obesity has debate.

This review provides gastroenterologists with a comprehensive evaluation of the obesity-related digestive diseases, including pathophysiology of carcinogenesis, obesity-related risk of each disease, and medical effect of weight reduction.


Excessive weight and adiposity induce increase of free fatty acid, leptin, plasminogen activator inhibitor 1 (PAI-1), tumor necrosis factor α (TNF-α), and resistin and decrease of adiponectin. This results in insulin resistance and increased insulin-like growth factor-binding protein 1 (IGFBP1) and IGFBP2. Consequently this increased insulin like growth factor 1 (IGF-1) bioavailability and inhibit apoptosis and increase cell proliferation on target cells.

1. Insulin and IGFs

Obesity is strongly related with insulin resistance, in which insulin and IGF-1 are elevated in obese persons. Increased circulating insulin/IGF1 and upregulation of insulin/IGF receptor signaling pathways are known to be related with the formation of many kinds of cancer.[7] Insulin induced proliferation of colon cancer cells in vitro,[8] while IGF-1 inhibits apoptosis, leading to the development of cancer.[9] Higher plasma IGF-1 and lower IGFBP-3 were associated with increased risk of colorectal cancer in a prospective cohort in both men and women.[10],[11] High serum C-peptide, a marker for insulin production, increased colorectal cancer risk.[12] Insulin increased IGF-1 that binds to IGF-1 receptor and insulin receptor. After IGF-1 binds IGF-1 receptor, it activates phosphoinositide 3-kinase (PI3K) and Akt/protein kinase B and indirectly activates mammalian target of rapamycin complex 1 (mTORC1). In addition, insulin receptor bind growth factor receptor-bound protein 2 (GRBP2) and activates Ras/Raf/extracellular signal-regulated kinase (ERK) pathway that induces cell proliferation.

A previous study suggested that metformin, oral antihyperglycemic agent, may reduce the risk of cancer.[13] One of suggested anticancer mechanisms of metformin is the inhibition of the mTORC1.[14] The mTOR signaling network plays a pivotal role in metabolism and proliferation of cancer cell.[15] The reduction of circulating insulin and IGF-1 by metformin may be associated with anticancer action.[16]

2. Adipokines

Adipokines are cytokines released from adipose tissue. Adipokines play roles in metabolic control (leptin, adiponectin, resistin, visfatin, retinol binding protein 4, apetin, vaspin, omentin, chemerin, acylation stimulating protein, and agouti signaling protein), inflammation (resistin, TNF, IL-6, IL-1, IL-10, IL-1 receptor antagonist, CCL2, CCL5, CXCL8, CXCL10, macrophage migration inhibitory factor, hepcidin, adipsin, and serum amyloid protein A), and tissue repair (angiotensin, renin, PAI-1, nerve growth factor, vascular endothelial growth factor, transforming growth factor β, hepatocyte growth factor, human epidermal growth factor, insulin like growth factor 1, and tissue factor).[17],[18]

Adipocyte-conditioned media can enhance tumorigenesis in cancer cells.[19] These tumorigenic effects of adipocyte seem to be mediated by adipokines such as adiponectin, leptin, TNF, IL-6, IL-8, IL-10, and IL-1 receptor agonists.[20]

1) Leptin

Leptin is an adipocyte-derived hormone that suppresses appetite and increase energy expenditure in hypothalamus and controls body weight.[21] Leptin regulates neuroendocrine axis and inflammatory responses.[22] Amount of body fat is directly correlated circulating leptin and serum leptin increase in obese individuals and drop during weight loss.[23] Leptin has six different leptin receptors: Ob-R, OB-Rb, OB-Rc, Ob-Rd, Ob-Re, and Ob-Rf.[24] OB-Rb mRNA encodes long form of leptin receptor (LEPR-B) and is expressed primarily in the hypothalamus but is also expressed in immune systems. After leptin binds to receptor (LEPR-B), conformational change of receptor activates Jak2 and auto-phosphrylates itself. This serves as a docking site for SHP2 (protein tyrosine phosphatase), STAT5, and STAT3. When SHP2, STAT5, and STAT3 bind to phosphorylated LEPR-B, they are activated by Jak2-mediated phosphorylation and they regulate energy homeostasis and body weight.

Several clinical studies suggested the tumorigenic effect of leptin. Higher plasma leptin levels are associated with esophageal adenocarcinoma (EAC),[25] colon cancer,[26] and endometrial cancer.[27] Increased serum leptin is associated with the recurrence of stage I/II HCC after curative treatment.[28]In vitro studies confirmed the regulation effect of leptin on tumorigenesis. Leptin enhances cell proliferation and angiogenesis in esophageal cancer cells,[29] colon cancer cells,[30] HCC cells,[31] and cholangiocarcinoma cells.[32]

2) Adiponectin

Adiponectin consists of four different molecular isoforms (i.e., trimer, hexamer, high molecular weight, and globular).[33] The biological effects of the isoforms are mainly mediated through two classical adiponectin receptor subtypes: AdipoR1 and AdipoR2.[34] The circulating level of adiponectin, secreted from visceral fat adipocytes, has inverse correlation with body mass index (BMI) and is usually higher in women than in men.[35],[36] Adiponectin is known as an insulin sensitizer and has antiangiogenic and anti-inflammatory activities. In vitro studies have suggested adiponectin involvement in various cancer cell types.[37] Adiponectin inhibits cell proliferation and induces apoptosis both in vitro and in vivo through different molecular pathways.[38] First, adiponectin inhibited colon cancer cell proliferation via AdipoR1- and AdipoR2-mediated AMP-activated protein kinase (AMPK) activation.[39] AMPK interferes with cellular growth signaling through mTOR, thus inhibiting carcinogenesis. Adiponectin activates AMPK in several cell lines promoting growth arrest and apoptosis via increased p53 and p21 expression. Second, tumor suppressor effects of adiponectin are also mediated via AKT and ERK signaling pathways in pancreatic beta cells and lung epithelial cells.[40],[41] Growth factors activate PI3K which results in the phosphorylation of AKT that promotes cellular growth and proliferation. Adiponectin has the molecular potential to antagonize the oncogenic actions of leptin by blocking downstream effector molecules in hepatocellular carcinogenesis.[42]

Several clinical studies have suggested that adiponectin has antitumor effects. The expression of adiponectin receptors was reported to be significantly higher in areas occupied by colorectal tumors.[43] Plasma adiponectin levels are inversely related with gastric cancer and metastasis.[44],[45] Lower tissue expression of adiponectin in HCC is associated with poor prognosis.[46] In a prospective study using the Nurses’ Health Study and the Health Professionals Follow-up Study among 616 incident colorectal cancer cases and 1,205 controls, plasma adiponectin was significantly associated with reduced risk of colorectal cancer among men.[47]

3) Resistin

Resistin, 12 kDa protein, is referred to as FIZZ3 and is a 108 amino acid prepeptid.[48] It is produced by peripheral blood mononuclear cells, macrophages, bone marrow, pancreatic cells, adipocytes, spleen, and muscles.[49] Resistin induces IL-1, IL-6, IL-8, IL-12, TNF, and Toll-like receptor 2 through the nuclear factor-κB pathway.[50] Circulating resistin level was higher in patients with colon cancer compared with control subjects.[51] High resistin is risk of breast cancer in pre- and post-menopausal females[52] and promotes growth and aggressiveness of tumor cells through STAT3 activation in breast cancer.[53]

4) Plasminogen activator inhibitor-1

PAI-1 is a protein that is encoded by the SERPINE1 gene. PAI-1 is mainly produced by the endothelium and is also secreted by adipose tissue. PAI-1 inhibits the activity of matrix metalloproteinases (MMPs), which play a crucial role in invasion and migration of malignant cells. PAI-1 modulates cell migration by regulating extracellular matrix (ECM) proteolysis.[54] PAI-1 inhibits plasmin production and sequentially inhibits MMP activation and induce ECM proteolysis and cell migration.[54] First, PAI-1 modulates migration through cell surface receptors such as low density lipoprotein receptor-related protein 1 (LRP1) and protease urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor (uPA/uPAR). PAI-1 binding to uPA/uPAR can also trigger the detachment of cell surface integrins from their ECM ligands and subsequent internalization in an LRP1-uPA/uPAR-dependent manner. Second, PAI-1 regulates cell adhesion through interactions with vitronectin.[54]

Overexpression PAI-1 has been found in esophageal and colorectal cancer.[55] Recently PAI-1 has been suggested as potential cancer therapeutic target.[56]

3. Immuomodulation

Obesity is associated with low-grade inflammation. Chronic inflammation associated with obesity modulates immune cell function.[57] Epithelial γδ T cell function is the guardians of the epithelial barrier and mediate repair.[58] Dysfunction in their function, and subsequently the deterioration of the epithelium can result in undesired consequences for the host. Obese patients are more prone to nonhealing injuries, infection, and disease. Adipocytes can modulate CD4(+) T-cell function through the release of lipids.[59] Free fatty acids were the most prominent modulators of T-cell proliferation. T-cell co-stimulation protects obesity-induced adipose inflammation and insulin resistance.[60]

The amount of adipocytokines produced by adipose tissue is strongly influenced by the immune cells present in adipose tissue.[61] Adipose tissue macrophage numbers increase in obese persons and participate in inflammatory pathways that are activated in adipose tissues.[62] The immune system plays a key role in antitumor activity and also can promote tumor development and progression under certain circumstances. The density of tumor-associated macrophages seems to be correlated with increased angiogenesis, tumor invasion, and poor prognosis.[63]


1. Gastroesophageal reflux disease

Obesity is a well-known risk factor for GERDs in both Asian and Western.[64],[65] Large epidemiological studies have demonstrated that obesity is an important risk factor of GERD.[64][66] Jacobson et al.[65] showed that subjects that reported at least weekly symptoms had a near linear increase in the adjusted OR for reflux symptoms for each BMI group. A large study using 8,571 Korean men, who underwent comprehensive screening and endoscopy, demonstrated that high BMI increased the risk of reflux esophagitis with dose-dependent pattern.[64] Furthermore, weight gain (increase of BMI >1) increased the risk of new development of reflux esophagitis.[64] In a small study, which 453 hospital employees responded GERD symptom questionnaires and 196 subjects underwent endoscopy, obesity was associated with reflux symptoms and esophagitis.[67]

Abdominal visceral adiposity, rather than BMI, appears to be more closely associated with reflux esophagitis.[3],[68] A large cross-sectional study using 5,329 comprehensive screening individuals demonstrated that odds ratio (OR) for erosive esophagitis correlated with obesity measured by BMI, waist circumference, and abdominal visceral adipose tissue volume (p<0.001 for each factor).[3] The multivariate OR for erosive esophagitis was 1.97 for a visceral adipose tissue volume of 500 to 999 cm3, 2.27 for 1,000 to 1,499 cm3, and 2.94 for ≥1,500 cm3, compared with participants who had visceral adipose tissue volumes less than 500 cm3.[3] When all three obesity indexes were analyzed simultaneously, abdominal visceral adipose tissue volume, but not BMI or waist circumference, was associated with erosive esophagitis.[3]

Pathophysiological mechanism in obesity include lower esophageal sphincter abnormalities, increased risk of hiatal hernia, and increased intragastric pressure. Additionally, alterations in the secretion of adiponectin and leptin from adipocytes is a proposed link between obesity and Barrett’s esophagus and EAC.

The data for weight reduction as a treatment for GERD is less robust, but weight reduction appears to be an association with fewer GERD symptoms. In lean person, diet-induced weight reduction correlated with improvement in reflux symptoms.[69] However, even modest weight reduction of 2 to 3 kg caused a remarkable improvement in GERD symptoms, suggesting that changes in diet rather than body weight may have been responsible for improvement of GERD symptom. In obese persons who had symptoms of GERD, diet-induced weight reduction did not improve symptoms or 24-hour esophageal pH values.[70] But weight reduction is related with improvement of erosive esophagitis in a large cohort study.[64] In contrast, the gastric bypass surgery consistently has shown to decrease GERD symptoms.[71][73]

2. Barrett’s esophagus and esophageal cancer

GERD and obesity are strong risk factors of EAC and BE. A landmark population-based case-control study showed that the risk of EAC was 8-fold greater in patients with recurrent GERD symptoms compared with those without GERD symptoms.[74] It is known that GERD can lead to erosive esophagitis, progressing to a metaplastic, specialized intestinal epithelium (Barrett’s esophagus).[75] BE progresses to EAC in a small portion, approximately 0.12% to 0.60% per year.[76][78] A meta-analysis of population-based studies demonstrated that weekly GERD symptoms increase EAC risk by approximately 5-fold.[79] Patients with longstanding symptoms, nocturnal symptoms, or more frequent symptoms are at higher risk. However, the severity of symptoms is not associated with an increased risk of EAC.

Obesity is a definite risk factor for EAC. A BMI of 30 to 34.9 kg/m2 is associated with a 2.4-fold increase in risk of EAC compared with a BMI of less than 25 kg/m2.[80] Abdominal obesity is associated with BE and EAC (OR, 2.51).[81] A recent Mendelian randomized study using 999 patients with EAC, 2,061 patients with BE, and 2,169 population controls demonstrated that EAC and BE risk increased by 16% (OR, 1.16) and 12% (OR, 1.12) per 1 kg/m2 increase in BMI.[82]

Obesity increased intraabdominal pressure and promoted formation of hiatal hernia, which is a strong risk factor of GERD.[83],[84] Abdominal obesity is associated with BE and EAC after adjusting for GERD.[80] In addition to mechanical effect, abdominal obesity changed circulating levels of inflammatory cytokines that are associated with BE and EAC.[85] Metabolic syndrome are associated with BE and EAC.[86],[87] IGF-1 pathway is strongly associated with EAC. Circulating IGFBP3 are inversely associated with BE.[88] A polymorphism in IGF-I gene is associated with BE,[89] and a polymorphism in IGF-I receptor modifies the effect of obesity on the risk of BE and EAC.[90] The IGF pathway is also involved in the risk of progression from BE to EAC.[91] Circulating levels of leptin also had an association with BE and progression of BE to EAC.[25],[79],[85],[92],[93] Decreased circulating level of adiponectin also seems to be associated with BE and progression to EAC in some, but not all, studies.[85],[92],[94],[95] Complex metabolic effects of obesity seem to have synergistic effects with GERD on the risk of BE and EAC.[96],[97]


Obesity is an important risk factor for colorectal adenoma and cancer. Previous studies showed a positive association between obesity measured by BMI and colorectal cancer,[98],[99] recent studies suggested that abdominal obesity and metabolic syndrome were stronger predictors of colorectal adenoma than BMI, a marker of general obesity.[100],[101] Visceral adipose tissue (VAT) is associated with insulin resistance and higher circulating levels of IGF-I, which may induce carcinogenesis by increased cell proliferation and reduced apoptosis.[102] Several studies demonstrated that direct measurement of VAT using computed tomography is a better predictor of insulin resistance or hypertension than waist circumference or BMI.[103],[104] Small studies were inconsistent about the association between VAT and colorectal neoplasia.[105][107] However, a large cross sectional study using 3,922 screening persons demonstrated colorectal adenoma had a positive association with VAT and high waist circumference when they were considered separately but only VAT contributed to colorectal adenoma when both were considered simultaneously.[4] Obesity measured by BMI seems to impose a greater risk of colorectal cancer for men than for women.[98],[108],[109] In a large study, colorectal adenoma had a dose-response correlation with VAT in both sexes, whereas it was related with metabolic syndrome, BMI, and waist circumference in men but not in women.[4] Women seem to accumulate less VAT with weight gain than men.[3],[110]

Large prospective cohort studies have demonstrated that obesity increases the risk of colorectal cancer by 1.5-fold compared to normal weight persons.[111] However, a recent Western study showed no association between BMI and CRC.[112] In sex-specific meta-analysis, the incidence of colorectal cancer was higher with obesity, with relative risk (RR) varying from 1.37 to 1.95 for CRC in men, whereas the association between obesity and CRC was weaker in women.[113][115] The incidence of CRC was higher in women with obesity in two of the three studies (RR, 1.15).[114][116] A pooled analysis using 300,000 Japanese subjects reported a significant association between BMI and CRC (HR [per 1 kg/m2 increase in BMI], 1.03 and 1.02 for men and women, respectively).[117] Two studies showed a significant increase in colon cancer in men but not women (HR [per 5 kg/m2 increase in BMI], 1.12 and 1.25).[118],[119] A recent Western study showed no association between BMI and CRC.[112] In summary, BMI appears to increase the risk of CRC in men, but less in women. This gender difference may be explained by a protective effect of estrogen attributable to apoptosis induction and cell proliferation inhibition[120] or differences in adipose tissue distribution, as the more pronounced visceral adiposity in men than in women.[121]


1. Nonalcoholic fatty liver disease

NAFLD is the most frequent chronic liver disease and its prevalence is 14% to 30% of the general population. Obesity is the most important risk factor for NAFLD. The prevalence of NAFLD is 4.6-fold in the obese population and up to 74% of obese individuals have fatty liver.[122] Among morbidly obese patients undergoing bariatric surgery for weight loss, 84% to 96% have NAFLD and 2% to 12% have severe fibrosis or cirrhosis.[123][125] NAFLD is also strongly associated with insulin resistance and metabolic syndrome.[126],[127] Among individuals with NAFLD, about 90% have features of metabolic syndrome.[128]

The development of NAFLD is known to be through a “two hit” process.[129],[130] The first “hit” includes accumulation of fat in hepatocytes, which is associated with insulin resistance, and fatty acid metabolism dysregulation that leads to steatosis. The second “hit” causes hepatocyte inflammation and necrosis, which can lead to cirrhosis and fibrosis.[129],[130]

The presence of hepatic steatosis, along with obesity and diabetes mellitus, seems to increase the risk of HCC in chronic HCV. Hepatic steatosis is one of established histopathologic features of chronic HCV with a prevalence from 31% to 72%.[131][134] A Japanese cohort study demonstrated that hepatic steatosis increases the risk for the development of HCC in chronic HCV (RR, 2.81) and BMI directly correlated with steatohepatitis.[135] In a Japanese cohort study consisted of 1,431 patients with chronic HCV following for up to 10 years, obesity is an independent risk factor for HCC development in chronic HCV.[136] The risk of HCC in chronic HCV increased in overweight patients (HR, 1.86) and obese patients (HR, 3.10) as compared to underweight patients.[136] Another Japanese cohort study demonstrated that diabetes mellitus, based on a positive 75 g oral glucose tolerance test, increased the risk of HCC development in chronic HCV.[137] NAFLD and its associated risk factors such as obesity and diabetes increase the risk of HCC development in chronic HCV.[138]

3. Cirrhosis and HCC

Several epidemiologic studies have suggested the possible link between diabetes mellitus and HCC.[139],[140] Many patients with diabetes have NAFLD, a risk factor for HCC. It seems that NAFLD causes HCC via cirrhosis, even if the exact pathogenesis is unclear. One study showed that features of nonalcoholic steatohepatitis (NASH) are more frequently observed in HCC arising in cryptogenic cirrhosis than in HCC patients of viral or alcoholic etiology.[141] HCC may be a late complication of NASH-induced cirrhosis. NAFLD, the predominant manifestation of metabolic syndrome in the liver can progress to cirrhosis and HCC.[142] Metformin decreases HCC risk in a dose-dependent manner in both population-based and in vitro studies.[143]


1. Gallstone and biliary cancer

Obesity is well known risk factor of cholesterol gallstone and exposes patients to increased risk of gallstone-related complications and cholecystectomy. Clinical and epidemiological studies have suggested that obesity is positively related with the risk of gallbladder cancer. Obesity may modulate lipid and endogenous hormones metabolism, affect gallbladder motility, increase the risk of gallstones, and also increased the risk of gallbladder cancer.[144]

Several epidemiologic studies suggested an association between diabetes mellitus and cholangiocarcinoma. A meta-analysis using 15 studies demonstrated that patients with diabetes had a higher risk of cholangiocarcinoma comparing to individuals without diabetes.[145] Another meta-analysis using nine articles (four case-control and five cohort studies) showed that patients with diabetes had an increased risk of extrahepatic cholangiocarcinoma (OR, 1.61 for case-control studies; RR, 1.61 for cohort studies).[146]

2. Pancreatic cancer

Several epidemiologic studies have suggested relationship of pancreatic cancer with high body mass and lack of physical activity.[147][149] High BMI (BMI of ≥30 kg/m2) was associated with an increased risk of pancreatic cancer compared with normal (BMI of <23 kg/m2). Moderate physical activity had an inverse relationship with pancreatic cancer comparing to the highest and lowest categories. Furthermore, high BMI is associated with decreased survival in patients with pancreatic cancer.[149],[150] Overweight or obese individuals develop pancreatic cancer at a younger age than persons with a normal weight.[149]


The association between obesity and gastric cancer has not been well studied. A meta-analysis from 10 studies with 9,492 gastric cancer and 3,097,794 total population demonstrated that obesity (BMI>25) was associated with an increased risk of gastric cancer (OR, 1.22).[151] In stratified analysis, obesity (BMI>25) was associated with an increased risk of cardia gastric cancer (OR, 1.55) and gastric cancer among non-Asians (OR, 1.24) but had no association with noncardia gastric cancer and Asian gastric cancers.

Another meta-analysis from 24 prospective studies with 41,791 cases demonstrated that both overweight (BMI, 25 to 30) and obesity (BMI≥30) were not associated with risk of total gastric cancer.[152] However, BMI was positively associated with the risk of gastric cardia cancer but not with gastric noncardia cancer. These results indicate that obesity is related with cardiac cancer but not with noncardiac cancer.


Meta-analysis of 21 studies comprising data from 77,538 individuals demonstrated obesity increased the risk of upper abdominal pain (OR, 2.65), gastroesophageal reflux (OR, 1.89), diarrhea (OR, 1.45), chest pain/heartburn (OR, 1.74), vomiting (OR, 1.76), retching (OR, 1.33), and incomplete evacuation (OR, 1.32), whereas all abdominal pain, lower abdominal pain, bloating, constipation/hard stools, fecal incontinence, nausea and anal blockage had no association with obesity.[153]

For Australian adults, the prevalence of 26 gastrointestinal symptoms was determined by a validated postal questionnaire which was sent to 5,000 randomly selected residents.[154] The response rate was 60%. The prevalence of obesity (BMI≥30 kg/m2) and overweight was 25.1% and 36.1%, respectively. The adjustment for socioeconomic characteristics and eating behaviors had a positive association with abdominal pain (OR, 1.34), esophageal symptoms (OR, 1.35), and diarrhea (OR, 1.86), whereas dysmotility symptoms and constipation had no association with obesity.[154] Of 3,927 invited subjects, 1,731 (44.1%) responded to the questionnaire to assess the occurrence of functional bowel (FB) symptoms in Northern Norway.[155] In a multivariate regression model, obesity increased the risk of FB (OR, 1.61).[155]

Upper abdominal pain may be related to postprandial stomach distention or delayed gastric emptying. Diarrhea may be related to increased food intake leading to increased osmotic loads and poor stool consistency.


Weight reduction improved metabolic syndrome and insulin resistance and subsequently may reduce the risk of obesity-related benign diseases.[156],[157] Many observational studies have shown that people who have a lower weight gain during adulthood have a lower risk of colon cancer, breast cancer, and endometrial cancer. Because most studies about whether weight reduction prevents cancer were from cohort and case-control studies, these observational studies can be difficult to interpret. Nevertheless, weight reduction has been recommended for cancer prevention in world-wide.

Obesity also may contribute to poor prognosis and low survival in obesity-related cancer patients. Weight reduction by bariatric surgery appear to reduce obesity-related benign disease and cancers in extreme obese perosons.[158][160] Also bariatric surgery in extreme obese patients reduced all-cause and cause-specific mortality.[161] The high effect of Bariatric surgery on obesity-related medical condition may be below; whereas most lifestyle modification result in weight reduction of less than 10 percent, bariatric surgery combined with lifestyle changes result in weight reduction of 30 percent.

In one observational study of 1,053 patients with stage III colorectal cancer, neither BMI nor weight change was significantly associated with an increased risk of cancer recurrence and death in patients with colon cancer.[162] In one cohort study of 25,291 colon cancer patients who received treatment in adjuvant chemotherapy trials, obesity and underweight status were associated independently with inferior outcomes.[163] Recent meta-analysis using eight studies showed that obesity is associated with poorer overall and breast cancer survival in pre- and post-menopausal breast cancer.[164]

Several studies about medical weight reduction strategies showed successful weight reduction in cancer patients. A telephone-based lifestyle interventions led to significant weight loss that was still evident at 24 months, without adverse effects on quality of life, hospitalizations, or medical events.[165] In a multicenter study using 692 overweight and obese women with breast cancer, a behavioral weight loss intervention can lead to clinically meaningful weight loss.[166] But it should be further evaluated whether these intentional medical weight reduction has potential benefit on cancer recurrence and survival or not. Nevertheless, intentional weight reduction has been recommended as one of the important life style modification in obesity-related cancers.


Overweight and obesity, particularly abdominal visceral obesity, increased the risk of a wide spectrum of benign digestive diseases such as GERD, BE, erosive esophagitis, NAFLD, gallstones, and pancreatitis and digestive organ cancers such as cholangiocarcinoma, HCC, pancreatic cancer, colorectal cancer, and esophageal cancer.

Both mechanical and humoral factors caused by obesity seem to be involved in the development of esophageal diseases, whereas pathophysiology of other digestive disorders seems to be related with obesity induced proinflammatory and inflammatory cytokines. Excessive weight and adiposity induce increase of free fatty acid, TNF-α, and resistin and decrease of adiponectin. This results in insulin resistance and altered IGF-1 pathway and inhibits apoptosis and increase cell proliferation on target cells.

Therefore weight reduction can improve the insulin resistance and subsequently seems to reduce the incidence of obesity-related cancer and mortality.


  1. VS MalikWC WillettFB HuGlobal obesity: trends, risk factors and policy implicationsNat Rev Endocrinol20139132710.1038/nrendo.2012.19923165161
  2. S FujiharaH MoriH KobaraMetabolic syndrome, obesity, and gastrointestinal cancerGastroenterol Res Pract2012201248362310.1155/2012/48362323304125
  3. SY NamIJ ChoiKH RyuBJ ParkHB KimBH NamAbdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and womenGastroenterology201013919021911.e210.1053/j.gastro.2010.08.01920727886
  4. SY NamBC KimKS HanAbdominal visceral adipose tissue predicts risk of colorectal adenoma in both sexesClin Gastroenterol Hepatol20108443450.e210.1016/j.cgh.2010.02.00120144736
  5. P ColicchioG TarantinoF del GenioNon-alcoholic fatty liver disease in young adult severely obese non-diabetic patients in South ItalyAnn Nutr Metab20054928929510.1159/00008729516088092
  6. KH SchmitzML NeuhouserT Agurs-CollinsImpact of obesity on cancer survivorship and the potential relevance of race and ethnicityJ Natl Cancer Inst20131051344135410.1093/jnci/djt22323990667
  7. D LeRoithR BasergaL HelmanCT Roberts JrInsulin-like growth factors and cancerAnn Intern Med1995122545910.7326/0003-4819-122-1-199501010-000097619109
  8. LF WatkinsLR LewisAE LevineCharacterization of the synergistic effect of insulin and transferrin and the regulation of their receptors on a human colon carcinoma cell lineInt J Cancer19904537237510.1002/ijc.29104502272406206
  9. R KaaksA LukanovaEnergy balance and cancer: the role of insulin and insulin-like growth factor-IProc Nutr Soc2001609110610.1079/PNS20007011310428
  10. J MaMN PollakE GiovannucciProspective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3J Natl Cancer Inst19999162062510.1093/jnci/91.7.62010203281
  11. E GiovannucciMN PollakEA PlatzA prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal neoplasia in womenCancer Epidemiol Biomarkers Prev2000934534910794477
  12. J MaE GiovannucciM PollakA prospective study of plasma C-peptide and colorectal cancer risk in menJ Natl Cancer Inst20049654655310.1093/jnci/djh08215069117
  13. MB SchneiderH MatsuzakiJ HaorahPrevention of pancreatic cancer induction in hamsters by metforminGastroenterology20011201263127010.1053/gast.2001.2325811266389
  14. J Sinnett-SmithK KisfalviR KuiE RozengurtMetformin inhibition of mTORC1 activation, DNA synthesis and proliferation in pancreatic cancer cells: dependence on glucose concentration and role of AMPKBiochem Biophys Res Commun201343035235710.1016/j.bbrc.2012.11.01023159620
  15. GG ChiangRT AbrahamTargeting the mTOR signaling network in cancerTrends Mol Med20071343344210.1016/j.molmed.2007.08.00117905659
  16. RM MemmottJR MercadoCR MaierS KawabataSD FoxPA DennisMetformin prevents tobacco carcinogen: induced lung tumorigenesisCancer Prev Res (Phila)201031066107610.1158/1940-6207.CAPR-10-005520810672
  17. K RabeM LehrkeKG ParhoferUC BroedlAdipokines and insulin resistanceMol Med20081474175110.2119/2008-00058.Rabe19009016
  18. R KrysiakG Handzlik-OrlikB OkopienThe role of adipokines in connective tissue diseasesEur J Nutr20125151352810.1007/s00394-012-0370-022584415
  19. SA AaronsonGrowth factors and cancerScience19912541146115310.1126/science.16597421659742
  20. H TilgAR MoschenAdipocytokines: mediators linking adipose tissue, inflammation and immunityNat Rev Immunol2006677278310.1038/nri193716998510
  21. H FengL ZhengZ FengY ZhaoN ZhangThe role of leptin in obesity and the potential for leptin replacement therapyEndocrine201344333910.1007/s12020-012-9865-y23274948
  22. G FantuzziR FaggioniLeptin in the regulation of immunity, inflammation, and hematopoiesisJ Leukoc Biol20006843744611037963
  23. JM FriedmanJL HalaasLeptin and the regulation of body weight in mammalsNature199839576377010.1038/273769796811
  24. M AmitaniA AsakawaH AmitaniA InuiThe role of leptin in the control of insulin-glucose axisFront Neurosci201375110.3389/fnins.2013.0005123579596
  25. C DugganL OnstadS HardikarPL BlountBJ ReidTL VaughanAssociation between markers of obesity and progression from Barrett’s esophagus to esophageal adenocarcinomaClin Gastroenterol Hepatol20131193494310.1016/j.cgh.2013.02.01723466711
  26. H EndoK HosonoT UchiyamaLeptin acts as a growth factor for colorectal tumours at stages subsequent to tumour initiation in murine colon carcinogenesisGut2011601363137110.1136/gut.2010.23575421406387
  27. CM DallalLA BrintonDC BauerObesity-related hormones and endometrial cancer among postmenopausal women: a nested case-control study within the B~FIT cohortEndocr Relat Cancer20132015116010.1530/ERC-12-022923222000
  28. N WatanabeK TakaiK ImaiIncreased levels of serum leptin are a risk factor for the recurrence of stage I/II hepatocellular carcinoma after curative treatmentJ Clin Biochem Nutr20114915315810.3164/jcbn.10-14922128212
  29. O OgunwobiG MutungiIL BealesLeptin stimulates proliferation and inhibits apoptosis in Barrett’s esophageal adenocarcinoma cells by cyclooxygenase-2-dependent, prostaglandin-E2-mediated transactivation of the epidermal growth factor receptor and c-Jun NH2-terminal kinase activationEndocrinology20061474505451610.1210/en.2006-022416740977
  30. T AparicioL KotelevetsA TsocasLeptin stimulates the proliferation of human colon cancer cells in vitro but does not promote the growth of colon cancer xenografts in nude mice or intestinal tumorigenesis in Apc(Min/+) miceGut2005541136114510.1136/gut.2004.06053315857934
  31. C ChenYC ChangCL LiuTP LiuKJ ChangIC GuoLeptin induces proliferation and anti-apoptosis in human hepatocarcinoma cells by up-regulating cyclin D1 and down-regulating Bax via a Janus kinase 2-linked pathwayEndocr Relat Cancer20071451352910.1677/ERC-06-002717639064
  32. G FavaG AlpiniC RychlickiLeptin enhances cholangiocarcinoma cell growthCancer Res2008686752676110.1158/0008-5472.CAN-07-668218701500
  33. G WolfNew insights into thiol-mediated regulation of adiponectin secretionNutr Rev20086664264510.1111/j.1753-4887.2008.00115.x19019026
  34. OO OgunwobiIL BealesGlobular adiponectin, acting via adiponectin receptor-1, inhibits leptin-stimulated oesophageal adenocarcinoma cell proliferationMol Cell Endocrinol2008285435010.1016/j.mce.2008.01.02318313838
  35. PA KernGB Di GregorioT LuN RassouliG RanganathanAdiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expressionDiabetes2003521779178510.2337/diabetes.52.7.177912829646
  36. SY NamCirculating inflammatory cytokines are associated with the risk of Barrett’s esophagus in Western personsJ Neurogastroenterol Motil20142055855910.5056/jnm1409825273126
  37. S ObeidL HebbardRole of adiponectin and its receptors in cancerCancer Biol Med2012921322023691481
  38. MP ScheidG SweeneyThe role of adiponectin signaling in metabolic syndrome and cancerRev Endocr Metab Disord20141515716710.1007/s11154-013-9265-524019064
  39. AY KimYS LeeKH KimAdiponectin represses colon cancer cell proliferation via AdipoR1- and -R2-mediated AMPK activationMol Endocrinol2010241441145210.1210/me.2009-049820444885
  40. N WijesekaraM KrishnamurthyA BhattacharjeeA SuhailG SweeneyMB WheelerAdiponectin-induced ERK and AKT phosphorylation protects against pancreatic beta cell apoptosis and increases insulin gene expression and secretionJ Biol Chem2010285336233363110.1074/jbc.M109.08508420709750
  41. E NigroO ScudieroD SarnataroAdiponectin affects lung epithelial A549 cell viability counteracting TNF alpha and IL-1beta toxicity through AdipoR1Int J Biochem Cell Biol2013451145115310.1016/j.biocel.2013.03.00323500159
  42. D SharmaJ WangPP FuAdiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesisHepatology2010521713172210.1002/hep.2389220941777
  43. K YonedaA TomimotoH EndoExpression of adiponectin receptors, AdipoR1 and AdipoR2, in normal colon epithelium and colon cancer tissueOncol Rep20082047948318695895
  44. M IshikawaJ KitayamaS KazamaT HiramatsuK HatanoH NagawaPlasma adiponectin and gastric cancerClin Cancer Res2005112 Pt 146647215701829
  45. M IshikawaJ KitayamaT YamauchiAdiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoR1 and AdipoR2Cancer Sci2007981120112710.1111/j.1349-7006.2007.00486.x17459059
  46. NK SaxenaPP FuA NagalingamAdiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinomaGastroenterology201013917621773.e510.1053/j.gastro.2010.07.00120637208
  47. M SongX ZhangK WuPlasma adiponectin and soluble leptin receptor and risk of colorectal cancer: a prospective studyCancer Prev Res (Phila)2013687588510.1158/1940-6207.CAPR-13-016923872505
  48. U MeierAM GressnerEndocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistinClin Chem2004501511152510.1373/clinchem.2004.03248215265818
  49. CM KusminskiPG McTernanS KumarRole of resistin in obesity, insulin resistance and type II diabetesClin Sci (Lond)200510924325610.1042/CS2005007816104844
  50. SE WozniakLL GeeMS WachtelEE FrezzaAdipose tissue: the new endocrine organ? A review articleDig Dis Sci2009541847185610.1007/s10620-008-0585-319052866
  51. G GonulluH KahramanA BedirA BektasI YücelAssociation between adiponectin, resistin, insulin resistance, and colorectal tumorsInt J Colorectal Dis20102520521210.1007/s00384-009-0828-619888587
  52. AM AssiriHF KamelMF HassanienResistin, visfatin, adiponectin, and leptin: risk of breast cancer in pre- and postmenopausal Saudi females and their possible diagnostic and predictive implications as novel biomarkersDis Markers2015201525351910.1155/2015/25351925838618
  53. SK DeshmukhSK SrivastavaA BhardwajResistin and interleukin-6 exhibit racially-disparate expression in breast cancer patients, display molecular association and promote growth and aggressiveness of tumor cells through STAT3 activationOncotarget20156112311124110.18632/oncotarget.359125868978
  54. RP CzekayCE Wilkins-PortSP HigginsPAI-1: an integrator of cell signaling and migrationInt J Cell Biol2011201156248110.1155/2011/56248121837240
  55. T SakakibaraK HibiM KoikePAI-1 expression levels in esophageal and colorectal cancers are closely correlated to those in corresponding normal tissuesAnticancer Res2006264343434717201153
  56. VR PlacencioYA DeClerckPlasminogen activator inhibitor-1 in cancer: rationale and insight for future therapeutic testingCancer Res2015752969297410.1158/0008-5472.CAN-15-087626180080
  57. KP CheungKR TaylorJM JamesonImmunomodulation at epithelial sites by obesity and metabolic diseaseImmunol Res20125218219910.1007/s12026-011-8261-722160809
  58. KR TaylorRE MillsAE CostanzoJM JamesonGammadelta T cells are reduced and rendered unresponsive by hyperglycemia and chronic TNFalpha in mouse models of obesity and metabolic diseasePLoS One20105e1142210.1371/journal.pone.001142220625397
  59. A Ioan-FacsinayJC KwekkeboomS WesthoffAdipocyte-derived lipids modulate CD4+ T-cell functionEur J Immunol2013431578158710.1002/eji.20124309623504601
  60. J ZhongX RaoZ BraunsteinT-cell costimulation protects obesity-induced adipose inflammation and insulin resistanceDiabetes2014631289130210.2337/db13-109424222350
  61. A SchäfflerU Müller-LadnerJ SchölmerichC BüchlerRole of adipose tissue as an inflammatory organ in human diseasesEndocr Rev20062744946710.1210/er.2005-002216684901
  62. SP WeisbergD McCannM DesaiM RosenbaumRL LeibelAW Ferrante JrObesity is associated with macrophage accumulation in adipose tissueJ Clin Invest20031121796180810.1172/JCI20031924614679176
  63. F BalkwillCancer and the chemokine networkNat Rev Cancer2004454055010.1038/nrc138815229479
  64. SY NamIJ ChoiBH NamKW ParkCG KimObesity and weight gain as risk factors for erosive oesophagitis in menAliment Pharmacol Ther2009291042105210.1111/j.1365-2036.2009.03965.x19222414
  65. BC JacobsonSC SomersCS FuchsCP KellyCA Camargo JrBody-mass index and symptoms of gastroesophageal reflux in womenN Engl J Med20063542340234810.1056/NEJMoa05439116738270
  66. GR Locke 3rdNJ TalleySL FettAR ZinsmeisterLJ Melton 3rdRisk factors associated with symptoms of gastroesophageal refluxAm J Med199910664264910.1016/S0002-9343(99)00121-710378622
  67. HB El-SeragDY GrahamJA SatiaL RabeneckObesity is an independent risk factor for GERD symptoms and erosive esophagitisAm J Gastroenterol20051001243125010.1111/j.1572-0241.2005.41703.x15929752
  68. SJ ChungD KimMJ ParkMetabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-upsGut2008571360136510.1136/gut.2007.14709018441006
  69. CA Fraser-MoodieB NortonC GornallS MagnagoAR WealeGK HolmesWeight loss has an independent beneficial effect on symptoms of gastrooesophageal reflux in patients who are overweightScand J Gastroenterol19993433734010.1080/00365529975002632610365891
  70. LM Mathus-VliegenGN TytgatTwenty-four-hour pH measurements in morbid obesity: effects of massive overweight, weight loss and gastric distensionEur J Gastroenterol Hepatol199686356408853250
  71. I RaftopoulosO AwaisAP CourcoulasJD LuketichLaparoscopic gastric bypass after antireflux surgery for the treatment of gastroesophageal reflux in morbidly obese patients: initial experienceObes Surg2004141373138010.1381/096089204258395015603654
  72. K ZainabadiAP CourcoulasO AwaisI RaftopoulosLaparoscopic revision of Nissen fundoplication to Roux-en-Y gastric bypass in morbidly obese patientsSurg Endosc2008222737274010.1007/s00464-008-9848-518363066
  73. KB Jones JrRoux-en-Y gastric bypass: an effective antireflux procedure in the less than morbidly obeseObes Surg19988353810.1381/0960892987655550249562484
  74. J LagergrenR BergströmA LindgrenO NyrénSymptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinomaN Engl J Med199934082583110.1056/NEJM19990318340110110080844
  75. RF SouzaK KrishnanSJ SpechlerAcid, bile, and CDX: the ABCs of making Barrett’s metaplasiaAm J Physiol Gastrointest Liver Physiol2008295G211G21810.1152/ajpgi.90250.200818556417
  76. F Hvid-JensenL PedersenAM DrewesHT SørensenP Funch-JensenIncidence of adenocarcinoma among patients with Barrett’s esophagusN Engl J Med20113651375138310.1056/NEJMoa110304221995385
  77. TK DesaiK KrishnanN SamalaThe incidence of oesophageal adenocarcinoma in non-dysplastic Barrett’s oesophagus: a meta-analysisGut20126197097610.1136/gutjnl-2011-30073021997553
  78. S WaniSR PuliNJ ShaheenEsophageal adenocarcinoma in Barrett’s esophagus after endoscopic ablative therapy: a meta-analysis and systematic reviewAm J Gastroenterol200910450251310.1038/ajg.2008.3119174812
  79. JH RubensteinJB TaylorMeta-analysis: the association of oesophageal adenocarcinoma with symptoms of gastrooesophageal refluxAliment Pharmacol Ther2010321222122710.1111/j.1365-2036.2010.04471.x20955441
  80. C HoyoMB CookF KamangarBody mass index in relation to oesophageal and oesophagogastric junction adenocarcinomas: a pooled analysis from the International BEACON ConsortiumInt J Epidemiol2012411706171810.1093/ije/dys17623148106
  81. S SinghAN SharmaMH MuradCentral adiposity is associated with increased risk of esophageal inflammation, metaplasia, and adenocarcinoma: a systematic review and meta-analysisClin Gastroenterol Hepatol20131113991412.e710.1016/j.cgh.2013.05.00923707461
  82. AP ThriftNJ ShaheenMD GammonObesity and risk of esophageal adenocarcinoma and Barrett’s esophagus: a Mendelian randomization studyJ Natl Cancer Inst2014106dju25210.1093/jnci/dju25225269698
  83. MH DerakhshanEV RobertsonJ FletcherMechanism of association between BMI and dysfunction of the gastrooesophageal barrier in patients with normal endoscopyGut20126133734310.1136/gutjnl-2011-30063321873737
  84. JE PandolfinoHB El-SeragQ ZhangN ShahSK GhoshPJ KahrilasObesity: a challenge to esophagogastric junction integrityGastroenterology200613063964910.1053/j.gastro.2005.12.01616530504
  85. JM GarciaAE SplenserJ KramerCirculating inflammatory cytokines and adipokines are associated with increased risk of Barrett’s esophagus: a case-control studyClin Gastroenterol Hepatol201412229238.e310.1016/j.cgh.2013.07.03823954649
  86. J DrahosW RickerR ParsonsRM PfeifferJL WarrenMB CookMetabolic syndrome increases risk of Barrett esophagus in the absence of gastroesophageal reflux: an analysis of SEER-Medicare dataJ Clin Gastroenterol20154928228810.1097/MCG.000000000000011924671095
  87. B LindkvistD JohansenT StocksMetabolic risk factors for esophageal squamous cell carcinoma and adenocarcinoma: a prospective study of 580,000 subjects within the Me-Can projectBMC Cancer20141410310.1186/1471-2407-14-10324548688
  88. KB GreerCL ThompsonL BrennerAssociation of insulin and insulin-like growth factors with Barrett’s oesophagusGut20126166567210.1136/gutjnl-2011-30064121930730
  89. AR McElholmAJ McKnightCC PattersonA population-based study of IGF axis polymorphisms and the esophageal inflammation, metaplasia, adenocarcinoma sequenceGastroenterology2010139204212.e310.1053/j.gastro.2010.04.01420403354
  90. K MacDonaldGA PorterDL GuernseyR ZhaoAG CassonA polymorphic variant of the insulin-like growth factor type I receptor gene modifies risk of obesity for esophageal adenocarcinomaCancer Epidemiol200933374010.1016/j.canep.2009.04.01419679045
  91. SH SiahpushTL VaughanJN LampeLongitudinal study of insulin-like growth factor, insulin-like growth factor binding protein-3, and their polymorphisms: risk of neoplastic progression in Barrett’s esophagusCancer Epidemiol Biomarkers Prev2007162387239510.1158/1055-9965.EPI-06-098618006928
  92. OM ThompsonSA BeresfordEA KirkMP BronnerTL VaughanSerum leptin and adiponectin levels and risk of Barrett’s esophagus and intestinal metaplasia of the gastroesophageal junctionObesity (Silver Spring)2010182204221110.1038/oby.2009.50820111023
  93. BJ KendallGA MacdonaldNK HaywardLeptin and the risk of Barrett’s oesophagusGut20085744845410.1136/gut.2007.13124318178609
  94. JH RubensteinJY KaoRD MadanickAssociation of adiponectin multimers with Barrett’s oesophagusGut2009581583158910.1136/gut.2008.17155319570765
  95. JH RubensteinA DahlkemperJY KaoA pilot study of the association of low plasma adiponectin and Barrett’s esophagusAm J Gastroenterol20081031358136410.1111/j.1572-0241.2008.01823.x18510610
  96. JH RubensteinH MorgensternD McConellAssociations of diabetes mellitus, insulin, leptin, and ghrelin with gastroesophageal reflux and Barrett’s esophagusGastroenterology201314512371244.e510.1053/j.gastro.2013.08.05223999171
  97. DC WhitemanS SadeghiN PandeyaCombined effects of obesity, acid reflux and smoking on the risk of adenocarcinomas of the oesophagusGut20085717318010.1136/gut.2007.13137517932103
  98. TK MurphyEE CalleC RodriguezHS KahnMJ ThunBody mass index and colon cancer mortality in a large prospective studyAm J Epidemiol200015284785410.1093/aje/152.9.84711085396
  99. EE CalleC RodriguezK Walker-ThurmondMJ ThunOverweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adultsN Engl J Med20033481625163810.1056/NEJMoa02142312711737
  100. Y KimY KimS LeeAn association between colonic adenoma and abdominal obesity: a cross-sectional studyBMC Gastroenterol20099410.1186/1471-230X-9-419144203
  101. JH KimYJ LimYH KimIs metabolic syndrome a risk factor for colorectal adenoma?Cancer Epidemiol Biomarkers Prev2007161543154610.1158/1055-9965.EPI-07-019917684126
  102. E GiovannucciInsulin, insulin-like growth factors and colon cancer: a review of the evidenceJ Nutr200113111 Suppl3109S320S11694656
  103. T HayashiEJ BoykoMJ McNeelyDL LeonettiSE KahnWY FujimotoVisceral adiposity, not abdominal subcutaneous fat area, is associated with an increase in future insulin resistance in Japanese AmericansDiabetes2008571269127510.2337/db07-137818299316
  104. T HayashiEJ BoykoDL LeonettiVisceral adiposity is an independent predictor of incident hypertension in Japanese AmericansAnn Intern Med2004140992100010.7326/0003-4819-140-12-200406150-0000815197016
  105. TH OhJS ByeonSJ MyungVisceral obesity as a risk factor for colorectal neoplasmJ Gastroenterol Hepatol20082341141710.1111/j.1440-1746.2007.05125.x17725596
  106. DA SassRE SchoenJL WeissfeldRelationship of visceral adipose tissue to recurrence of adenomatous polypsAm J Gastroenterol20049968769310.1111/j.1572-0241.2004.04136.x15089903
  107. E ErarslanC TurkayA KoktenerC KocaB UzN BavbekAssociation of visceral fat accumulation and adiponectin levels with colorectal neoplasiaDig Dis Sci20095486286810.1007/s10620-008-0440-618716871
  108. EE FrezzaMS WachtelM Chiriva-InternatiInfluence of obesity on the risk of developing colon cancerGut20065528529110.1136/gut.2005.07316316239255
  109. RL AhmedKH SchmitzKE AndersonWD RosamondAR FolsomThe metabolic syndrome and risk of incident colorectal cancerCancer2006107283610.1002/cncr.2195016721800
  110. BL WajchenbergSubcutaneous and visceral adipose tissue: their relation to the metabolic syndromeEndocr Rev20002169773810.1210/edrv.21.6.041511133069
  111. T MizoueM InoueK WakaiAlcohol drinking and colorectal cancer in Japanese: a pooled analysis of results from five cohort studiesAm J Epidemiol20081671397140610.1093/aje/kwn07318420544
  112. A BurtonR MartinB GalobardesG Davey SmithM JeffreysYoung adulthood body mass index and risk of cancer in later adulthood: historical cohort studyCancer Causes Control2010212069207710.1007/s10552-010-9625-320680433
  113. DJ HarrissG AtkinsonK GeorgeLifestyle factors and colorectal cancer risk (1): systematic review and meta-analysis of associations with body mass indexColorectal Dis20091154756310.1111/j.1463-1318.2009.01766.x19207714
  114. Z DaiYC XuL NiuObesity and colorectal cancer risk: a meta-analysis of cohort studiesWorld J Gastroenterol2007134199420610.3748/wjg.v13.i31.419917696248
  115. DP GuhW ZhangN BansbackZ AmarsiCL BirminghamAH AnisThe incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysisBMC Public Health200998810.1186/1471-2458-9-8819320986
  116. AA MoghaddamM WoodwardR HuxleyObesity and risk of colorectal cancer: a meta-analysis of 31 studies with 70,000 eventsCancer Epidemiol Biomarkers Prev2007162533254710.1158/1055-9965.EPI-07-070818086756
  117. K MatsuoT MizoueK TanakaAssociation between body mass index and the colorectal cancer risk in Japan: pooled analysis of population-based cohort studies in JapanAnn Oncol20122347949010.1093/annonc/mdr14321597097
  118. JK BassettG SeveriDR EnglishBody size, weight change, and risk of colon cancerCancer Epidemiol Biomarkers Prev2010192978298610.1158/1055-9965.EPI-10-054320870733
  119. I LaakeI ThuneR SelmerS TretliML SlatteryMB VeierødA prospective study of body mass index, weight change, and risk of cancer in the proximal and distal colonCancer Epidemiol Biomarkers Prev2010191511152210.1158/1055-9965.EPI-09-081320501754
  120. J ChenD IversonEstrogen in obesity-associated colon cancer: friend or foe? Protecting postmenopausal women but promoting late-stage colon cancerCancer Causes Control2012231767177310.1007/s10552-012-0066-z23011535
  121. EE CalleObesity and cancerBMJ20073351107110810.1136/bmj.39384.472072.8017986715
  122. P AnguloKD LindorNon-alcoholic fatty liver diseaseJ Gastroenterol Hepatol200217 SupplS186S19010.1046/j.1440-1746.17.s1.10.x12000605
  123. JB DixonPS BhathalPE O’BrienNonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obeseGastroenterology20011219110010.1053/gast.2001.2554011438497
  124. PM GholamDP KotlerLJ FlancbaumLiver pathology in morbidly obese patients undergoing Roux-en-Y gastric bypass surgeryObes Surg200212495110.1381/09608920232114457711868297
  125. C BeymerKV KowdleyA LarsonP EdmonsonEP DellingerDR FlumPrevalence and predictors of asymptomatic liver disease in patients undergoing gastric bypass surgeryArch Surg20031381240124410.1001/archsurg.138.11.124014609874
  126. E BugianesiA GastaldelliE VanniInsulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanismsDiabetologia20054863464210.1007/s00125-005-1682-x15747110
  127. S LiangpunsakulN ChalasaniUnexplained elevations in alanine aminotransferase in individuals with the metabolic syndrome: results from the third National Health and Nutrition Survey (NHANES III)Am J Med Sci200532911111610.1097/00000441-200503000-0000115767815
  128. G MarchesiniE BugianesiG ForlaniNonalcoholic fatty liver, steatohepatitis, and the metabolic syndromeHepatology20033791792310.1053/jhep.2003.5016112668987
  129. D PapandreouI RoussoI MavromichalisUpdate on non-alcoholic fatty liver disease in childrenClin Nutr20072640941510.1016/j.clnu.2007.02.00217449148
  130. CP DayOF JamesSteatohepatitis: a tale of two “hits”?Gastroenterology199811484284510.1016/S0016-5085(98)70599-29547102
  131. AI GomaaSA KhanMB ToledanoI WakedSD Taylor-RobinsonHepatocellular carcinoma: epidemiology, risk factors and pathogenesisWorld J Gastroenterol2008144300430810.3748/wjg.14.430018666317
  132. DM ParkinGlobal cancer statistics in the year 2000Lancet Oncol2001253354310.1016/S1470-2045(01)00486-711905707
  133. HB El-SeragAC MasonRising incidence of hepatocellular carcinoma in the United StatesN Engl J Med199934074575010.1056/NEJM19990311340100110072408
  134. FX BoschJ RibesM DíazR ClériesPrimary liver cancer: worldwide incidence and trendsGastroenterology20041275 Suppl 1S5S1610.1053/j.gastro.2004.09.01115508102
  135. K OhataK HamasakiK ToriyamaHepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infectionCancer2003973036304310.1002/cncr.1142712784339
  136. T OhkiR TateishiT SatoObesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patientsClin Gastroenterol Hepatol2008645946410.1016/j.cgh.2008.02.01218387499
  137. I KonishiY HiasaS ShigematsuDiabetes pattern on the 75 g oral glucose tolerance test is a risk factor for hepatocellular carcinoma in patients with hepatitis C virusLiver Int2009291194120110.1111/j.1478-3231.2009.02043.x19422477
  138. S CaldwellSH ParkThe epidemiology of hepatocellular cancer: from the perspectives of public health problem to tumor biologyJ Gastroenterol200944 Suppl 199610110.1007/s00535-008-2258-619148801
  139. HB El-SeragT TranJE EverhartDiabetes increases the risk of chronic liver disease and hepatocellular carcinomaGastroenterology200412646046810.1053/j.gastro.2003.10.06514762783
  140. MS LaiMS HsiehYH ChiuTH ChenType 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infectionHepatology2006431295130210.1002/hep.2120816729295
  141. E BugianesiN LeoneE VanniExpanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinomaGastroenterology200212313414010.1053/gast.2002.3416812105842
  142. AB SiegelAX ZhuMetabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential linkCancer20091155651566110.1002/cncr.2468719834957
  143. HP ChenJJ ShiehCC ChangMetformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studiesGut20136260661510.1136/gutjnl-2011-30170822773548
  144. F WangB WangL QiaoAssociation between obesity and gall-bladder cancerFront Biosci (Landmark Ed)2012172550255810.2741/407022652797
  145. W JingG JinX ZhouDiabetes mellitus and increased risk of cholangiocarcinoma: a meta-analysisEur J Cancer Prev201221243110.1097/CEJ.0b013e3283481d8921857525
  146. LF ZhangHX ZhaoDiabetes mellitus and increased risk of extrahepatic cholangiocarcinoma: a meta-analysisHepatogastroenterology20136068468723321031
  147. U NöthlingsLR WilkensSP MurphyJH HankinBE HendersonLN KolonelBody mass index and physical activity as risk factors for pancreatic cancer: the multiethnic cohort studyCancer Causes Control20071816517510.1007/s10552-006-0100-017219012
  148. DS MichaudE GiovannucciWC WillettGA ColditzMJ StampferCS FuchsPhysical activity, obesity, height, and the risk of pancreatic cancerJAMA200128692192910.1001/jama.286.8.92111509056
  149. D LiJS MorrisJ LiuBody mass index and risk, age of onset, and survival in patients with pancreatic cancerJAMA20093012553256210.1001/jama.2009.88619549972
  150. RR McWilliamsME MatsumotoPA BurchObesity adversely affects survival in pancreatic cancer patientsCancer20101165054506210.1002/cncr.2546520665496
  151. P YangY ZhouB ChenOverweight, obesity and gastric cancer risk: results from a meta-analysis of cohort studiesEur J Cancer2009452867287310.1016/j.ejca.2009.04.01919427197
  152. Y ChenL LiuX WangBody mass index and risk of gastric cancer: a meta-analysis of a population with more than ten million from 24 prospective studiesCancer Epidemiol Biomarkers Prev2013221395140810.1158/1055-9965.EPI-13-004223697611
  153. GD EslickGastrointestinal symptoms and obesity: a meta-analysisObes Rev20121346947910.1111/j.1467-789X.2011.00969.x22188520
  154. GD EslickNJ TalleyPrevalence and relationship between gastrointestinal symptoms among individuals of different body mass index: a population-based studyObes Res Clin Pract20161014315010.1016/j.orcp.2015.05.01826142872
  155. RK BreckanAM AsfeldtB StraumeJ FlorholmenEJ PaulssenPrevalence, comorbidity, and risk factors for functional bowel symptoms: a population-based survey in Northern NorwayScand J Gastroenterol2012471274128210.3109/00365521.2012.68821523061445
  156. HS ParkSJ SimJY ParkEffect of weight reduction on metabolic syndrome in Korean obese patientsJ Korean Med Sci20041920220810.3346/jkms.2004.19.2.20215082891
  157. L BusettoVisceral obesity and the metabolic syndrome: effects of weight lossNutr Metab Cardiovasc Dis20011119520411590996
  158. G BowerT TomaL HarlingBariatric surgery and non-alcoholic fatty liver disease: a systematic review of liver biochemistry and histologyObes Surg2015252280228910.1007/s11695-015-1691-x25917981
  159. A MaestroM RiglaA CaixàsDoes bariatric surgery reduce cancer risk? A review of the literatureEndocrinol Nutr20156213814310.1016/j.endonu.2014.12.00525637364
  160. DE ArterburnAP CourcoulasBariatric surgery for obesity and metabolic conditions in adultsBMJ2014349g396110.1136/bmj.g396125164369
  161. TD AdamsTS MehtaLE DavidsonSC HuntAll-cause and cause-specific mortality associated with bariatric surgery: a reviewCurr Atheroscler Rep2015177410.1007/s11883-015-0551-426496931
  162. JA MeyerhardtD NiedzwieckiD HollisImpact of body mass index and weight change after treatment on cancer recurrence and survival in patients with stage III colon cancer: findings from Cancer and Leukemia Group B 89803J Clin Oncol2008264109411510.1200/JCO.2007.15.668718757324
  163. FA SinicropeNR FosterG YothersBody mass index at diagnosis and survival among colon cancer patients enrolled in clinical trials of adjuvant chemotherapyCancer20131191528153610.1002/cncr.2793823310947
  164. DS ChanAR VieiraD AuneBody mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studiesAnn Oncol2014251901191410.1093/annonc/mdu04224769692
  165. PJ GoodwinRJ SegalM VallisRandomized trial of a telephone-based weight loss intervention in postmenopausal women with breast cancer receiving letrozole: the LISA trialJ Clin Oncol2014322231223910.1200/JCO.2013.53.151724934783
  166. CL RockSW FlattTE ByersResults of the exercise and nutrition to enhance recovery and good health for you (ENERGY) trial: a behavioral weight loss intervention in overweight or obese breast cancer survivorsJ Clin Oncol2015333169317610.1200/JCO.2015.61.109526282657
The underlying source XML for this text is taken from https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5417774/fullTextXML. The license for the article is Creative Commons Attribution-NonCommercial. The main subject has been identified as obesity.