Beagle Obesity Navigating Weight Related Digestive Problems

By Isabella Storyclaire

last updated November 18, 2024

Contributions sourced from

Obesity-Related Digestive Diseases and Their Pathophysiology

Gut Liver. 2017 May; 11(3): 323334.

Obesity-Related Digestive Diseases and Their Pathophysiology

Department of Gastroenterology, Gastric Cancer Center, Kyungpook National University Medical Center, Daegu, Korea

Correspondence to: Su Youn Nam, Department of Gastroenterology, Gastric Cancer Center, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, 807 Hoguk-ro, Buk-gu, Daegu 41404, Korea, Tel: +82-53-200-2610, Fax: +82-53-200-2028, E-mail:

moc.liamg@41113102man

Received 2015 Nov 1; Accepted 2015 Dec 25.

2017 by The Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, Korean College of Helicobacter and Upper Gastrointestinal Research, Korean Association the Study of Intestinal Diseases, the Korean Association for the Study of the Liver, Korean Pancreatobiliary Association, and Korean Society of Gastrointestinal Cancer.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (

http://creativecommons.org/licenses/by-nc/4.0

) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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, Barretts 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.

Keywords: Obesity, Gastrointestinal disease, Cytokines

INTRODUCTION

The prevalence of global obesity among both women and men increased from 1980 to 2008 ().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), Barretts 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 ().²⁵ Obesity and related comorbid conditions may also increase risk for common adverse treatment effects in cancer patient.⁶

Estimates of obesity prevalence in women (A) and men (B). Among women, obesity prevalence has increased in all regions. The greatest magnitudes of increase (>20%) were observed in central Latin America, North America, North Africa, and the Middle East. For men, obesity has increased in all regions except South Asia. The greatest magnitude of increase was observed in North America, with an increase of >18%. Adapted from Malik VS, et al. Nat Rev Endocrinol 2013;9:1327, with permission from Nature Publishing Group.¹

Medical effect of obesity on digestive diseases. Obesity increases free fatty acids and alters adipocy-tokines. This metabolic alteration induces metabolic syndrome, including insulin resistance, dyslipidemia, and hypertension. Metabolic alteration and metabolic syndrome contribute to benign and malignant digestive disease. Mechanical effect of obesity may contribute to esophageal disease and several gastrointestinal symptoms.

GERD, gastroesophageal reflux disease; BE, Barretts esophagus; GI, gastrointestinal; NAFLD, non-alcoholic fatty liver disease; HCV, hepatitis C virus; EAC, esophageal adenocarcinoma; HCC, hepatocellular carcinoma.

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.

PATHOPHYSIOLOGY OF CARCINOGENESIS BY OBESITY

Excessive weight and adiposity induce increase of free fatty acid, leptin, plasminogen activator inhibitor 1 (PAI-1), tumor necrosis factor (TNF-), 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 , 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.²⁸In 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-B 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 females⁵² 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 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

ESOPHAGEAL DISEASE

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.⁶⁴⁶⁶ 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 Barretts 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.⁷¹⁷³

2. Barretts 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 (Barretts esophagus).⁷⁵ BE progresses to EAC in a small portion, approximately 0.12% to 0.60% per year.⁷⁶⁷⁸ 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

COLORECTAL ADENOMA AND CANCER

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.¹⁰⁵¹⁰⁷ 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.¹¹³¹¹⁵ The incidence of CRC was higher in women with obesity in two of the three studies (RR, 1.15).¹¹⁴¹¹⁶ 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 inhibition¹²⁰ or differences in adipose tissue distribution, as the more pronounced visceral adiposity in men than in women.¹²¹

LIVER DISEASE

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.¹²³¹²⁵ 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

2. Advanced hepatitis C-related disease

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%.¹³¹¹³⁴ 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

PANCREATO-BILIARY DISEASE

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.¹⁴⁷¹⁴⁹ 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

GASTRIC CANCER

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 (BMI30) 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.

FUNCTIONAL GASTROINTESTINAL DISEASE

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 (BMI30 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.

METABOLIC AND MEDICAL EFFECT OF WEIGHT REDUCTION

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.¹⁵⁸¹⁶⁰ 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.

CONCLUSIONS

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-, 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.

Footnotes

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

REFERENCES

Malik VS, Willett WC, Hu FB. Global obesity: trends, risk factors and policy implications. Nat Rev Endocrinol. 2013;9:1327. doi:10.1038/nrendo.2012.199. [PubMed] [CrossRef] [Google Scholar]

Fujihara S, Mori H, Kobara H, et al. Metabolic syndrome, obesity, and gastrointestinal cancer. Gastroenterol Res Pract. 2012;2012:483623. doi:10.1155/2012/483623. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Nam SY, Choi IJ, Ryu KH, Park BJ, Kim HB, Nam BH. Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women. Gastroenterology. 2010;139:19021911.e2. doi:10.1053/j.gastro.2010.08.019. [PubMed] [CrossRef] [Google Scholar]

Nam SY, Kim BC, Han KS, et al. Abdominal visceral adipose tissue predicts risk of colorectal adenoma in both sexes. Clin Gastroenterol Hepatol. 2010;8:443450.e2. doi:10.1016/j.cgh.2010.02.001. [PubMed] [CrossRef] [Google Scholar]

Colicchio P, Tarantino G, del Genio F, et al. Non-alcoholic fatty liver disease in young adult severely obese non-diabetic patients in South Italy. Ann Nutr Metab. 2005;49:289295. doi:10.1159/000087295. [PubMed] [CrossRef] [Google Scholar]

Schmitz KH, Neuhouser ML, Agurs-Collins T, et al. Impact of obesity on cancer survivorship and the potential relevance of race and ethnicity. J Natl Cancer Inst. 2013;105:13441354. doi:10.1093/jnci/djt223. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

LeRoith D, Baserga R, Helman L, Roberts CT., Jr Insulin-like growth factors and cancer. Ann Intern Med. 1995;122:5459. doi:10.7326/0003-4819-122-1-199501010-00009. [PubMed] [CrossRef] [Google Scholar]

Watkins LF, Lewis LR, Levine AE. Characterization of the synergistic effect of insulin and transferrin and the regulation of their receptors on a human colon carcinoma cell line. Int J Cancer. 1990;45:372375. doi:10.1002/ijc.2910450227. [PubMed] [CrossRef] [Google Scholar]

Kaaks R, Lukanova A. Energy balance and cancer: the role of insulin and insulin-like growth factor-I. Proc Nutr Soc. 2001;60:91106. doi:10.1079/PNS200070. [PubMed] [CrossRef] [Google Scholar]

10.

Ma J, Pollak MN, Giovannucci E, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst. 1999;91:620625. doi:10.1093/jnci/91.7.620. [PubMed] [CrossRef] [Google Scholar]

11.

Giovannucci E, Pollak MN, Platz EA, et al. A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal neoplasia in women. Cancer Epidemiol Biomarkers Prev. 2000;9:345349. [PubMed] [Google Scholar]

12.

Ma J, Giovannucci E, Pollak M, et al. A prospective study of plasma C-peptide and colorectal cancer risk in men. J Natl Cancer Inst. 2004;96:546553. doi:10.1093/jnci/djh082. [PubMed] [CrossRef] [Google Scholar]

13.

Schneider MB, Matsuzaki H, Haorah J, et al. Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology. 2001;120:12631270. doi:10.1053/gast.2001.23258. [PubMed] [CrossRef] [Google Scholar]

14.

Sinnett-Smith J, Kisfalvi K, Kui R, Rozengurt E. Metformin inhibition of mTORC1 activation, DNA synthesis and proliferation in pancreatic cancer cells: dependence on glucose concentration and role of AMPK. Biochem Biophys Res Commun. 2013;430:352357. doi:10.1016/j.bbrc.2012.11.010. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

15.

Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer. Trends Mol Med. 2007;13:433442. doi:10.1016/j.molmed.2007.08.001. [PubMed] [CrossRef] [Google Scholar]

16.

Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen: induced lung tumorigenesis. Cancer Prev Res (Phila) 2010;3:10661076. doi:10.1158/1940-6207.CAPR-10-0055. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

20.

Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006;6:772783. doi:10.1038/nri1937. [PubMed] [CrossRef] [Google Scholar]

21.

Feng H, Zheng L, Feng Z, Zhao Y, Zhang N. The role of leptin in obesity and the potential for leptin replacement therapy. Endocrine. 2013;44:3339. doi:10.1007/s12020-012-9865-y. [PubMed] [CrossRef] [Google Scholar]

22.

Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol. 2000;68:437446. [PubMed] [Google Scholar]

23.

Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395:763770. doi:10.1038/27376. [PubMed] [CrossRef] [Google Scholar]

25.

Duggan C, Onstad L, Hardikar S, Blount PL, Reid BJ, Vaughan TL. Association between markers of obesity and progression from Barretts esophagus to esophageal adenocarcinoma. Clin Gastroenterol Hepatol. 2013;11:934943. doi:10.1016/j.cgh.2013.02.017. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

26.

Endo H, Hosono K, Uchiyama T, et al. Leptin acts as a growth factor for colorectal tumours at stages subsequent to tumour initiation in murine colon carcinogenesis. Gut. 2011;60:13631371. doi:10.1136/gut.2010.235754. [PubMed] [CrossRef] [Google Scholar]

27.

Dallal CM, Brinton LA, Bauer DC, et al. Obesity-related hormones and endometrial cancer among postmenopausal women: a nested case-control study within the B~FIT cohort. Endocr Relat Cancer. 2013;20:151160. doi:10.1530/ERC-12-0229. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

28.

Watanabe N, Takai K, Imai K, et al. Increased levels of serum leptin are a risk factor for the recurrence of stage I/II hepatocellular carcinoma after curative treatment. J Clin Biochem Nutr. 2011;49:153158. doi:10.3164/jcbn.10-149. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

29.

Ogunwobi O, Mutungi G, Beales IL. Leptin stimulates proliferation and inhibits apoptosis in Barretts esophageal adenocarcinoma cells by cyclooxygenase-2-dependent, prostaglandin-E2-mediated transactivation of the epidermal growth factor receptor and c-Jun NH2-terminal kinase activation. Endocrinology. 2006;147:45054516. doi:10.1210/en.2006-0224. [PubMed] [CrossRef] [Google Scholar]

30.

Aparicio T, Kotelevets L, Tsocas A, et al. Leptin 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/+) mice. Gut. 2005;54:11361145. doi:10.1136/gut.2004.060533. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

31.

Chen C, Chang YC, Liu CL, Liu TP, Chang KJ, Guo IC. Leptin induces proliferation and anti-apoptosis in human hepatocarcinoma cells by up-regulating cyclin D1 and down-regulating Bax via a Janus kinase 2-linked pathway. Endocr Relat Cancer. 2007;14:513529. doi:10.1677/ERC-06-0027. [PubMed] [CrossRef] [Google Scholar]

33.

Wolf G. New insights into thiol-mediated regulation of adiponectin secretion. Nutr Rev. 2008;66:642645. doi:10.1111/j.1753-4887.2008.00115.x. [PubMed] [CrossRef] [Google Scholar]

34.

Ogunwobi OO, Beales IL. Globular adiponectin, acting via adiponectin receptor-1, inhibits leptin-stimulated oesophageal adenocarcinoma cell proliferation. Mol Cell Endocrinol. 2008;285:4350. doi:10.1016/j.mce.2008.01.023. [PubMed] [CrossRef] [Google Scholar]

35.

Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan G. Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes. 2003;52:17791785. doi:10.2337/diabetes.52.7.1779. [PubMed] [CrossRef] [Google Scholar]

36.

Nam SY. Circulating inflammatory cytokines are associated with the risk of Barretts esophagus in Western persons. J Neurogastroenterol Motil. 2014;20:558559. doi:10.5056/jnm14098. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

38.

Scheid MP, Sweeney G. The role of adiponectin signaling in metabolic syndrome and cancer. Rev Endocr Metab Disord. 2014;15:157167. doi:10.1007/s11154-013-9265-5. [PubMed] [CrossRef] [Google Scholar]

39.

Kim AY, Lee YS, Kim KH, et al. Adiponectin represses colon cancer cell proliferation via AdipoR1- and -R2-mediated AMPK activation. Mol Endocrinol. 2010;24:14411452. doi:10.1210/me.2009-0498. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

40.

Wijesekara N, Krishnamurthy M, Bhattacharjee A, Suhail A, Sweeney G, Wheeler MB. Adiponectin-induced ERK and AKT phosphorylation protects against pancreatic beta cell apoptosis and increases insulin gene expression and secretion. J Biol Chem. 2010;285:3362333631. doi:10.1074/jbc.M109.085084. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

41.

Nigro E, Scudiero O, Sarnataro D, et al. Adiponectin affects lung epithelial A549 cell viability counteracting TNF alpha and IL-1beta toxicity through AdipoR1. Int J Biochem Cell Biol. 2013;45:11451153. doi:10.1016/j.biocel.2013.03.003. [PubMed] [CrossRef] [Google Scholar]

42.

Sharma D, Wang J, Fu PP, et al. Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis. Hepatology. 2010;52:17131722. doi:10.1002/hep.23892. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

43.

Yoneda K, Tomimoto A, Endo H, et al. Expression of adiponectin receptors, AdipoR1 and AdipoR2, in normal colon epithelium and colon cancer tissue. Oncol Rep. 2008;20:479483. [PubMed] [Google Scholar]

44.

Ishikawa M, Kitayama J, Kazama S, Hiramatsu T, Hatano K, Nagawa H. Plasma adiponectin and gastric cancer. Clin Cancer Res. 2005;11(2 Pt 1):466472. [PubMed] [Google Scholar]

45.

Ishikawa M, Kitayama J, Yamauchi T, et al. Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoR1 and AdipoR2. Cancer Sci. 2007;98:11201127. doi:10.1111/j.1349-7006.2007.00486.x. [PubMed] [CrossRef] [Google Scholar]

46.

Saxena NK, Fu PP, Nagalingam A, et al. Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma. Gastroenterology. 2010;139:17621773.e5. doi:10.1053/j.gastro.2010.07.001. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

47.

Song M, Zhang X, Wu K, et al. Plasma adiponectin and soluble leptin receptor and risk of colorectal cancer: a prospective study. Cancer Prev Res (Phila) 2013;6:875885. doi:10.1158/1940-6207.CAPR-13-0169. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

48.

Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem. 2004;50:15111525. doi:10.1373/clinchem.2004.032482. [PubMed] [CrossRef] [Google Scholar]

49.

Kusminski CM, McTernan PG, Kumar S. Role of resistin in obesity, insulin resistance and type II diabetes. Clin Sci (Lond) 2005;109:243256. doi:10.1042/CS20050078. [PubMed] [CrossRef] [Google Scholar]

50.

Wozniak SE, Gee LL, Wachtel MS, Frezza EE. Adipose tissue: the new endocrine organ? A review article. Dig Dis Sci. 2009;54:18471856. doi:10.1007/s10620-008-0585-3. [PubMed] [CrossRef] [Google Scholar]

51.

Gonullu G, Kahraman H, Bedir A, Bektas A, Ycel I. Association between adiponectin, resistin, insulin resistance, and colorectal tumors. Int J Colorectal Dis. 2010;25:205212. doi:10.1007/s00384-009-0828-6. [PubMed] [CrossRef] [Google Scholar]

52.

Assiri AM, Kamel HF, Hassanien MF. Resistin, visfatin, adiponectin, and leptin: risk of breast cancer in pre- and postmenopausal Saudi females and their possible diagnostic and predictive implications as novel biomarkers. Dis Markers. 2015;2015:253519. doi:10.1155/2015/253519. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

53.

Deshmukh SK, Srivastava SK, Bhardwaj A, et al. Resistin and interleukin-6 exhibit racially-disparate expression in breast cancer patients, display molecular association and promote growth and aggressiveness of tumor cells through STAT3 activation. Oncotarget. 2015;6:1123111241. doi:10.18632/oncotarget.3591. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

54.

Czekay RP, Wilkins-Port CE, Higgins SP, et al. PAI-1: an integrator of cell signaling and migration. Int J Cell Biol. 2011;2011:562481. doi:10.1155/2011/562481. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

55.

Sakakibara T, Hibi K, Koike M, et al. PAI-1 expression levels in esophageal and colorectal cancers are closely correlated to those in corresponding normal tissues. Anticancer Res. 2006;26:43434347. [PubMed] [Google Scholar]

56.

Placencio VR, DeClerck YA. Plasminogen activator inhibitor-1 in cancer: rationale and insight for future therapeutic testing. Cancer Res. 2015;75:29692974. doi:10.1158/0008-5472.CAN-15-0876. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

57.

Cheung KP, Taylor KR, Jameson JM. Immunomodulation at epithelial sites by obesity and metabolic disease. Immunol Res. 2012;52:182199. doi:10.1007/s12026-011-8261-7. [PubMed] [CrossRef] [Google Scholar]

58.

Taylor KR, Mills RE, Costanzo AE, Jameson JM. Gammadelta T cells are reduced and rendered unresponsive by hyperglycemia and chronic TNFalpha in mouse models of obesity and metabolic disease. PLoS One. 2010;5:e11422. doi:10.1371/journal.pone.0011422. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

59.

Ioan-Facsinay A, Kwekkeboom JC, Westhoff S, et al. Adipocyte-derived lipids modulate CD4+ T-cell function. Eur J Immunol. 2013;43:15781587. doi:10.1002/eji.201243096. [PubMed] [CrossRef] [Google Scholar]

60.

Zhong J, Rao X, Braunstein Z, et al. T-cell costimulation protects obesity-induced adipose inflammation and insulin resistance. Diabetes. 2014;63:12891302. doi:10.2337/db13-1094. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

61.

Schffler A, Mller-Ladner U, Schlmerich J, Bchler C. Role of adipose tissue as an inflammatory organ in human diseases. Endocr Rev. 2006;27:449467. doi:10.1210/er.2005-0022. [PubMed] [CrossRef] [Google Scholar]

62.

Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW., Jr Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:17961808. doi:10.1172/JCI200319246. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

63.

Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4:540550. doi:10.1038/nrc1388. [PubMed] [CrossRef] [Google Scholar]

64.

Nam SY, Choi IJ, Nam BH, Park KW, Kim CG. Obesity and weight gain as risk factors for erosive oesophagitis in men. Aliment Pharmacol Ther. 2009;29:10421052. doi:10.1111/j.1365-2036.2009.03965.x. [PubMed] [CrossRef] [Google Scholar]

65.

Jacobson BC, Somers SC, Fuchs CS, Kelly CP, Camargo CA., Jr Body-mass index and symptoms of gastroesophageal reflux in women. N Engl J Med. 2006;354:23402348. doi:10.1056/NEJMoa054391. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

66.

Locke GR, 3rd, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ., 3rd Risk factors associated with symptoms of gastroesophageal reflux. Am J Med. 1999;106:642649. doi:10.1016/S0002-9343(99)00121-7. [PubMed] [CrossRef] [Google Scholar]

67.

El-Serag HB, Graham DY, Satia JA, Rabeneck L. Obesity is an independent risk factor for GERD symptoms and erosive esophagitis. Am J Gastroenterol. 2005;100:12431250. doi:10.1111/j.1572-0241.2005.41703.x. [PubMed] [CrossRef] [Google Scholar]

68.

Chung SJ, Kim D, Park MJ, et al. Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups. Gut. 2008;57:13601365. doi:10.1136/gut.2007.147090. [PubMed] [CrossRef] [Google Scholar]

69.

Fraser-Moodie CA, Norton B, Gornall C, Magnago S, Weale AR, Holmes GK. Weight loss has an independent beneficial effect on symptoms of gastrooesophageal reflux in patients who are overweight. Scand J Gastroenterol. 1999;34:337340. doi:10.1080/003655299750026326. [PubMed] [CrossRef] [Google Scholar]

70.

Mathus-Vliegen LM, Tytgat GN. Twenty-four-hour pH measurements in morbid obesity: effects of massive overweight, weight loss and gastric distension. Eur J Gastroenterol Hepatol. 1996;8:635640. [PubMed] [Google Scholar]

71.

Raftopoulos I, Awais O, Courcoulas AP, Luketich JD. Laparoscopic gastric bypass after antireflux surgery for the treatment of gastroesophageal reflux in morbidly obese patients: initial experience. Obes Surg. 2004;14:13731380. doi:10.1381/0960892042583950. [PubMed] [CrossRef] [Google Scholar]

72.

Zainabadi K, Courcoulas AP, Awais O, Raftopoulos I. Laparoscopic revision of Nissen fundoplication to Roux-en-Y gastric bypass in morbidly obese patients. Surg Endosc. 2008;22:27372740. doi:10.1007/s00464-008-9848-5. [PubMed] [CrossRef] [Google Scholar]

73.

Jones KB., Jr Roux-en-Y gastric bypass: an effective antireflux procedure in the less than morbidly obese. Obes Surg. 1998;8:3538. doi:10.1381/096089298765555024. [PubMed] [CrossRef] [Google Scholar]

74.

Lagergren J, Bergstrm R, Lindgren A, Nyrn O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999;340:825831. doi:10.1056/NEJM199903183401101. [PubMed] [CrossRef] [Google Scholar]

75.

Souza RF, Krishnan K, Spechler SJ. Acid, bile, and CDX: the ABCs of making Barretts metaplasia. Am J Physiol Gastrointest Liver Physiol. 2008;295:G211G218. doi:10.1152/ajpgi.90250.2008. [PubMed] [CrossRef] [Google Scholar]

76.

Hvid-Jensen F, Pedersen L, Drewes AM, Srensen HT, Funch-Jensen P. Incidence of adenocarcinoma among patients with Barretts esophagus. N Engl J Med. 2011;365:13751383. doi:10.1056/NEJMoa1103042. [PubMed] [CrossRef] [Google Scholar]

77.

Desai TK, Krishnan K, Samala N, et al. The incidence of oesophageal adenocarcinoma in non-dysplastic Barretts oesophagus: a meta-analysis. Gut. 2012;61:970976. doi:10.1136/gutjnl-2011-300730. [PubMed] [CrossRef] [Google Scholar]

78.

Wani S, Puli SR, Shaheen NJ, et al. Esophageal adenocarcinoma in Barretts esophagus after endoscopic ablative therapy: a meta-analysis and systematic review. Am J Gastroenterol. 2009;104:502513. doi:10.1038/ajg.2008.31. [PubMed] [CrossRef] [Google Scholar]

79.

Rubenstein JH, Taylor JB. Meta-analysis: the association of oesophageal adenocarcinoma with symptoms of gastrooesophageal reflux. Aliment Pharmacol Ther. 2010;32:12221227. doi:10.1111/j.1365-2036.2010.04471.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

80.

Hoyo C, Cook MB, Kamangar F, et al. Body mass index in relation to oesophageal and oesophagogastric junction adenocarcinomas: a pooled analysis from the International BEACON Consortium. Int J Epidemiol. 2012;41:17061718. doi:10.1093/ije/dys176. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

81.

Singh S, Sharma AN, Murad MH, et al. Central adiposity is associated with increased risk of esophageal inflammation, metaplasia, and adenocarcinoma: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2013;11:13991412.e7. doi:10.1016/j.cgh.2013.05.009. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

82.

Thrift AP, Shaheen NJ, Gammon MD, et al. Obesity and risk of esophageal adenocarcinoma and Barretts esophagus: a Mendelian randomization study. J Natl Cancer Inst. 2014;106:dju252. doi:10.1093/jnci/dju252. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

83.

Derakhshan MH, Robertson EV, Fletcher J, et al. Mechanism of association between BMI and dysfunction of the gastrooesophageal barrier in patients with normal endoscopy. Gut. 2012;61:337343. doi:10.1136/gutjnl-2011-300633. [PubMed] [CrossRef] [Google Scholar]

84.

Pandolfino JE, El-Serag HB, Zhang Q, Shah N, Ghosh SK, Kahrilas PJ. Obesity: a challenge to esophagogastric junction integrity. Gastroenterology. 2006;130:639649. doi:10.1053/j.gastro.2005.12.016. [PubMed] [CrossRef] [Google Scholar]

85.

Garcia JM, Splenser AE, Kramer J, et al. Circulating inflammatory cytokines and adipokines are associated with increased risk of Barretts esophagus: a case-control study. Clin Gastroenterol Hepatol. 2014;12:229238.e3. doi:10.1016/j.cgh.2013.07.038. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

86.

Drahos J, Ricker W, Parsons R, Pfeiffer RM, Warren JL, Cook MB. Metabolic syndrome increases risk of Barrett esophagus in the absence of gastroesophageal reflux: an analysis of SEER-Medicare data. J Clin Gastroenterol. 2015;49:282288. doi:10.1097/MCG.0000000000000119. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

87.

Lindkvist B, Johansen D, Stocks T, et al. Metabolic risk factors for esophageal squamous cell carcinoma and adenocarcinoma: a prospective study of 580,000 subjects within the Me-Can project. BMC Cancer. 2014;14:103. doi:10.1186/1471-2407-14-103. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

88.

Greer KB, Thompson CL, Brenner L, et al. Association of insulin and insulin-like growth factors with Barretts oesophagus. Gut. 2012;61:665672. doi:10.1136/gutjnl-2011-300641. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

89.

McElholm AR, McKnight AJ, Patterson CC, et al. A population-based study of IGF axis polymorphisms and the esophageal inflammation, metaplasia, adenocarcinoma sequence. Gastroenterology. 2010;139:204212.e3. doi:10.1053/j.gastro.2010.04.014. [PubMed] [CrossRef] [Google Scholar]

90.

MacDonald K, Porter GA, Guernsey DL, Zhao R, Casson AG. A polymorphic variant of the insulin-like growth factor type I receptor gene modifies risk of obesity for esophageal adenocarcinoma. Cancer Epidemiol. 2009;33:3740. doi:10.1016/j.canep.2009.04.014. [PubMed] [CrossRef] [Google Scholar]

91.

Siahpush SH, Vaughan TL, Lampe JN, et al. Longitudinal study of insulin-like growth factor, insulin-like growth factor binding protein-3, and their polymorphisms: risk of neoplastic progression in Barretts esophagus. Cancer Epidemiol Biomarkers Prev. 2007;16:23872395. doi:10.1158/1055-9965.EPI-06-0986. [PubMed] [CrossRef] [Google Scholar]

92.

Thompson OM, Beresford SA, Kirk EA, Bronner MP, Vaughan TL. Serum leptin and adiponectin levels and risk of Barretts esophagus and intestinal metaplasia of the gastroesophageal junction. Obesity (Silver Spring) 2010;18:22042211. doi:10.1038/oby.2009.508. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

93.

Kendall BJ, Macdonald GA, Hayward NK, et al. Leptin and the risk of Barretts oesophagus. Gut. 2008;57:448454. doi:10.1136/gut.2007.131243. [PubMed] [CrossRef] [Google Scholar]

94.

Rubenstein JH, Kao JY, Madanick RD, et al. Association of adiponectin multimers with Barretts oesophagus. Gut. 2009;58:15831589. doi:10.1136/gut.2008.171553. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

95.

Rubenstein JH, Dahlkemper A, Kao JY, et al. A pilot study of the association of low plasma adiponectin and Barretts esophagus. Am J Gastroenterol. 2008;103:13581364. doi:10.1111/j.1572-0241.2008.01823.x. [PubMed] [CrossRef] [Google Scholar]

96.

Rubenstein JH, Morgenstern H, McConell D, et al. Associations of diabetes mellitus, insulin, leptin, and ghrelin with gastroesophageal reflux and Barretts esophagus. Gastroenterology. 2013;145:12371244.e5. doi:10.1053/j.gastro.2013.08.052. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

97.

Whiteman DC, Sadeghi S, Pandeya N, et al. Combined effects of obesity, acid reflux and smoking on the risk of adenocarcinomas of the oesophagus. Gut. 2008;57:173180. doi:10.1136/gut.2007.131375. [PubMed] [CrossRef] [Google Scholar]

98.

Murphy TK, Calle EE, Rodriguez C, Kahn HS, Thun MJ. Body mass index and colon cancer mortality in a large prospective study. Am J Epidemiol. 2000;152:847854. doi:10.1093/aje/152.9.847. [PubMed] [CrossRef] [Google Scholar]

99.

Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:16251638. doi:10.1056/NEJMoa021423. [PubMed] [CrossRef] [Google Scholar]

100.

Kim Y, Kim Y, Lee S. An association between colonic adenoma and abdominal obesity: a cross-sectional study. BMC Gastroenterol. 2009;9:4. doi:10.1186/1471-230X-9-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

101.

Kim JH, Lim YJ, Kim YH, et al. Is metabolic syndrome a risk factor for colorectal adenoma? Cancer Epidemiol Biomarkers Prev. 2007;16:15431546. doi:10.1158/1055-9965.EPI-07-0199. [PubMed] [CrossRef] [Google Scholar]

102.

Giovannucci E. Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr. 2001;131(11 Suppl):3109S320S. [PubMed] [Google Scholar]

103.

Hayashi T, Boyko EJ, McNeely MJ, Leonetti DL, Kahn SE, Fujimoto WY. Visceral adiposity, not abdominal subcutaneous fat area, is associated with an increase in future insulin resistance in Japanese Americans. Diabetes. 2008;57:12691275. doi:10.2337/db07-1378. [PubMed] [CrossRef] [Google Scholar]

104.

Hayashi T, Boyko EJ, Leonetti DL, et al. Visceral adiposity is an independent predictor of incident hypertension in Japanese Americans. Ann Intern Med. 2004;140:9921000. doi:10.7326/0003-4819-140-12-200406150-00008. [PubMed] [CrossRef] [Google Scholar]

105.

Oh TH, Byeon JS, Myung SJ, et al. Visceral obesity as a risk factor for colorectal neoplasm. J Gastroenterol Hepatol. 2008;23:411417. doi:10.1111/j.1440-1746.2007.05125.x. [PubMed] [CrossRef] [Google Scholar]

106.

Sass DA, Schoen RE, Weissfeld JL, et al. Relationship of visceral adipose tissue to recurrence of adenomatous polyps. Am J Gastroenterol. 2004;99:687693. doi:10.1111/j.1572-0241.2004.04136.x. [PubMed] [CrossRef] [Google Scholar]

107.

Erarslan E, Turkay C, Koktener A, Koca C, Uz B, Bavbek N. Association of visceral fat accumulation and adiponectin levels with colorectal neoplasia. Dig Dis Sci. 2009;54:862868. doi:10.1007/s10620-008-0440-6. [PubMed] [CrossRef] [Google Scholar]

109.

Ahmed RL, Schmitz KH, Anderson KE, Rosamond WD, Folsom AR. The metabolic syndrome and risk of incident colorectal cancer. Cancer. 2006;107:2836. doi:10.1002/cncr.21950. [PubMed] [CrossRef] [Google Scholar]

110.

Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev. 2000;21:697738. doi:10.1210/edrv.21.6.0415. [PubMed] [CrossRef] [Google Scholar]

111.

Mizoue T, Inoue M, Wakai K, et al. Alcohol drinking and colorectal cancer in Japanese: a pooled analysis of results from five cohort studies. Am J Epidemiol. 2008;167:13971406. doi:10.1093/aje/kwn073. [PubMed] [CrossRef] [Google Scholar]

112.

Burton A, Martin R, Galobardes B, Davey Smith G, Jeffreys M. Young adulthood body mass index and risk of cancer in later adulthood: historical cohort study. Cancer Causes Control. 2010;21:20692077. doi:10.1007/s10552-010-9625-3. [PubMed] [CrossRef] [Google Scholar]

113.

Harriss DJ, Atkinson G, George K, et al. Lifestyle factors and colorectal cancer risk (1): systematic review and meta-analysis of associations with body mass index. Colorectal Dis. 2009;11:547563. doi:10.1111/j.1463-1318.2009.01766.x. [PubMed] [CrossRef] [Google Scholar]

114.

Dai Z, Xu YC, Niu L. Obesity and colorectal cancer risk: a meta-analysis of cohort studies. World J Gastroenterol. 2007;13:41994206. doi:10.3748/wjg.v13.i31.4199. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

115.

Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 2009;9:88. doi:10.1186/1471-2458-9-88. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

116.

Moghaddam AA, Woodward M, Huxley R. Obesity and risk of colorectal cancer: a meta-analysis of 31 studies with 70,000 events. Cancer Epidemiol Biomarkers Prev. 2007;16:25332547. doi:10.1158/1055-9965.EPI-07-0708. [PubMed] [CrossRef] [Google Scholar]

117.

Matsuo K, Mizoue T, Tanaka K, et al. Association between body mass index and the colorectal cancer risk in Japan: pooled analysis of population-based cohort studies in Japan. Ann Oncol. 2012;23:479490. doi:10.1093/annonc/mdr143. [PubMed] [CrossRef] [Google Scholar]

118.

Bassett JK, Severi G, English DR, et al. Body size, weight change, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev. 2010;19:29782986. doi:10.1158/1055-9965.EPI-10-0543. [PubMed] [CrossRef] [Google Scholar]

119.

Laake I, Thune I, Selmer R, Tretli S, Slattery ML, Veierd MB. A prospective study of body mass index, weight change, and risk of cancer in the proximal and distal colon. Cancer Epidemiol Biomarkers Prev. 2010;19:15111522. doi:10.1158/1055-9965.EPI-09-0813. [PubMed] [CrossRef] [Google Scholar]

120.

Chen J, Iverson D. Estrogen in obesity-associated colon cancer: friend or foe? Protecting postmenopausal women but promoting late-stage colon cancer. Cancer Causes Control. 2012;23:17671773. doi:10.1007/s10552-012-0066-z. [PubMed] [CrossRef] [Google Scholar]

122.

Angulo P, Lindor KD. Non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2002;17( Suppl):S186S190. doi:10.1046/j.1440-1746.17.s1.10.x. [PubMed] [CrossRef] [Google Scholar]

123.

Dixon JB, Bhathal PS, OBrien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121:91100. doi:10.1053/gast.2001.25540. [PubMed] [CrossRef] [Google Scholar]

124.

Gholam PM, Kotler DP, Flancbaum LJ. Liver pathology in morbidly obese patients undergoing Roux-en-Y gastric bypass surgery. Obes Surg. 2002;12:4951. doi:10.1381/096089202321144577. [PubMed] [CrossRef] [Google Scholar]

125.

Beymer C, Kowdley KV, Larson A, Edmonson P, Dellinger EP, Flum DR. Prevalence and predictors of asymptomatic liver disease in patients undergoing gastric bypass surgery. Arch Surg. 2003;138:12401244. doi:10.1001/archsurg.138.11.1240. [PubMed] [CrossRef] [Google Scholar]

126.

Bugianesi E, Gastaldelli A, Vanni E, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia. 2005;48:634642. doi:10.1007/s00125-005-1682-x. [PubMed] [CrossRef] [Google Scholar]

127.

Liangpunsakul S, Chalasani N. Unexplained elevations in alanine aminotransferase in individuals with the metabolic syndrome: results from the third National Health and Nutrition Survey (NHANES III) Am J Med Sci. 2005;329:111116. doi:10.1097/00000441-200503000-00001. [PubMed] [CrossRef] [Google Scholar]

128.

Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917923. doi:10.1053/jhep.2003.50161. [PubMed] [CrossRef] [Google Scholar]

129.

Papandreou D, Rousso I, Mavromichalis I. Update on non-alcoholic fatty liver disease in children. Clin Nutr. 2007;26:409415. doi:10.1016/j.clnu.2007.02.002. [PubMed] [CrossRef] [Google Scholar]

130.

Day CP, James OF. Steatohepatitis: a tale of two hits? Gastroenterology. 1998;114:842845. doi:10.1016/S0016-5085(98)70599-2. [PubMed] [CrossRef] [Google Scholar]

131.

Gomaa AI, Khan SA, Toledano MB, Waked I, Taylor-Robinson SD. Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol. 2008;14:43004308. doi:10.3748/wjg.14.4300. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

132.

Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol. 2001;2:533543. doi:10.1016/S1470-2045(01)00486-7. [PubMed] [CrossRef] [Google Scholar]

133.

El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745750. doi:10.1056/NEJM199903113401001. [PubMed] [CrossRef] [Google Scholar]

134.

Bosch FX, Ribes J, Daz M, Clries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127(5 Suppl 1):S5S16. doi:10.1053/j.gastro.2004.09.011. [PubMed] [CrossRef] [Google Scholar]

135.

Ohata K, Hamasaki K, Toriyama K, et al. Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer. 2003;97:30363043. doi:10.1002/cncr.11427. [PubMed] [CrossRef] [Google Scholar]

136.

Ohki T, Tateishi R, Sato T, et al. Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients. Clin Gastroenterol Hepatol. 2008;6:459464. doi:10.1016/j.cgh.2008.02.012. [PubMed] [CrossRef] [Google Scholar]

137.

Konishi I, Hiasa Y, Shigematsu S, et al. Diabetes pattern on the 75 g oral glucose tolerance test is a risk factor for hepatocellular carcinoma in patients with hepatitis C virus. Liver Int. 2009;29:11941201. doi:10.1111/j.1478-3231.2009.02043.x. [PubMed] [CrossRef] [Google Scholar]

138.

Caldwell S, Park SH. The epidemiology of hepatocellular cancer: from the perspectives of public health problem to tumor biology. J Gastroenterol. 2009;44( Suppl 19):96101. doi:10.1007/s00535-008-2258-6. [PubMed] [CrossRef] [Google Scholar]

139.

El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126:460468. doi:10.1053/j.gastro.2003.10.065. [PubMed] [CrossRef] [Google Scholar]

140.

Lai MS, Hsieh MS, Chiu YH, Chen TH. Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection. Hepatology. 2006;43:12951302. doi:10.1002/hep.21208. [PubMed] [CrossRef] [Google Scholar]

141.

Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134140. doi:10.1053/gast.2002.34168. [PubMed] [CrossRef] [Google Scholar]

142.

Siegel AB, Zhu AX. Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer. 2009;115:56515661. doi:10.1002/cncr.24687. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

143.

Chen HP, Shieh JJ, Chang CC, et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut. 2013;62:606615. doi:10.1136/gutjnl-2011-301708. [PubMed] [CrossRef] [Google Scholar]

144.

Wang F, Wang B, Qiao L. Association between obesity and gall-bladder cancer. Front Biosci (Landmark Ed) 2012;17:25502558. doi:10.2741/4070. [PubMed] [CrossRef] [Google Scholar]

145.

Jing W, Jin G, Zhou X, et al. Diabetes mellitus and increased risk of cholangiocarcinoma: a meta-analysis. Eur J Cancer Prev. 2012;21:2431. doi:10.1097/CEJ.0b013e3283481d89. [PubMed] [CrossRef] [Google Scholar]

146.

Zhang LF, Zhao HX. Diabetes mellitus and increased risk of extrahepatic cholangiocarcinoma: a meta-analysis. Hepatogastroenterology. 2013;60:684687. [PubMed] [Google Scholar]

147.

Nthlings U, Wilkens LR, Murphy SP, Hankin JH, Henderson BE, Kolonel LN. Body mass index and physical activity as risk factors for pancreatic cancer: the multiethnic cohort study. Cancer Causes Control. 2007;18:165175. doi:10.1007/s10552-006-0100-0. [PubMed] [CrossRef] [Google Scholar]

148.

Michaud DS, Giovannucci E, Willett WC, Colditz GA, Stampfer MJ, Fuchs CS. Physical activity, obesity, height, and the risk of pancreatic cancer. JAMA. 2001;286:921929. doi:10.1001/jama.286.8.921. [PubMed] [CrossRef] [Google Scholar]

149.

Li D, Morris JS, Liu J, et al. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA. 2009;301:25532562. doi:10.1001/jama.2009.886. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

150.

McWilliams RR, Matsumoto ME, Burch PA, et al. Obesity adversely affects survival in pancreatic cancer patients. Cancer. 2010;116:50545062. doi:10.1002/cncr.25465. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

151.

Yang P, Zhou Y, Chen B, et al. Overweight, obesity and gastric cancer risk: results from a meta-analysis of cohort studies. Eur J Cancer. 2009;45:28672873. doi:10.1016/j.ejca.2009.04.019. [PubMed] [CrossRef] [Google Scholar]

152.

Chen Y, Liu L, Wang X, et al. Body mass index and risk of gastric cancer: a meta-analysis of a population with more than ten million from 24 prospective studies. Cancer Epidemiol Biomarkers Prev. 2013;22:13951408. doi:10.1158/1055-9965.EPI-13-0042. [PubMed] [CrossRef] [Google Scholar]

153.

Eslick GD. Gastrointestinal symptoms and obesity: a meta-analysis. Obes Rev. 2012;13:469479. doi:10.1111/j.1467-789X.2011.00969.x. [PubMed] [CrossRef] [Google Scholar]

154.

Eslick GD, Talley NJ. Prevalence and relationship between gastrointestinal symptoms among individuals of different body mass index: a population-based study. Obes Res Clin Pract. 2016;10:143150. doi:10.1016/j.orcp.2015.05.018. [PubMed] [CrossRef] [Google Scholar]

155.

Breckan RK, Asfeldt AM, Straume B, Florholmen J, Paulssen EJ. Prevalence, comorbidity, and risk factors for functional bowel symptoms: a population-based survey in Northern Norway. Scand J Gastroenterol. 2012;47:12741282. doi:10.3109/00365521.2012.688215. [PubMed] [CrossRef] [Google Scholar]

156.

Park HS, Sim SJ, Park JY. Effect of weight reduction on metabolic syndrome in Korean obese patients. J Korean Med Sci. 2004;19:202208. doi:10.3346/jkms.2004.19.2.202. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

157.

Busetto L. Visceral obesity and the metabolic syndrome: effects of weight loss. Nutr Metab Cardiovasc Dis. 2001;11:195204. [PubMed] [Google Scholar]

158.

Bower G, Toma T, Harling L, et al. Bariatric surgery and non-alcoholic fatty liver disease: a systematic review of liver biochemistry and histology. Obes Surg. 2015;25:22802289. doi:10.1007/s11695-015-1691-x. [PubMed] [CrossRef] [Google Scholar]

159.

Maestro A, Rigla M, Caixs A. Does bariatric surgery reduce cancer risk? A review of the literature. Endocrinol Nutr. 2015;62:138143. doi:10.1016/j.endonu.2014.12.005. [PubMed] [CrossRef] [Google Scholar]

161.

Adams TD, Mehta TS, Davidson LE, Hunt SC. All-cause and cause-specific mortality associated with bariatric surgery: a review. Curr Atheroscler Rep. 2015;17:74. doi:10.1007/s11883-015-0551-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

162.

Meyerhardt JA, Niedzwiecki D, Hollis D, et al. Impact 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 89803. J Clin Oncol. 2008;26:41094115. doi:10.1200/JCO.2007.15.6687. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

163.

Sinicrope FA, Foster NR, Yothers G, et al. Body mass index at diagnosis and survival among colon cancer patients enrolled in clinical trials of adjuvant chemotherapy. Cancer. 2013;119:15281536. doi:10.1002/cncr.27938. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

164.

Chan DS, Vieira AR, Aune D, et al. Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol. 2014;25:19011914. doi:10.1093/annonc/mdu042. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

165.

Goodwin PJ, Segal RJ, Vallis M, et al. Randomized trial of a telephone-based weight loss intervention in postmenopausal women with breast cancer receiving letrozole: the LISA trial. J Clin Oncol. 2014;32:22312239. doi:10.1200/JCO.2013.53.1517. [PubMed] [CrossRef] [Google Scholar]

166.

Rock CL, Flatt SW, Byers TE, et al. Results 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 survivors. J Clin Oncol. 2015;33:31693176. doi:10.1200/JCO.2015.61.1095. [PMC free article] [PubMed] [CrossRef] [Google Scholar]