Gastrointestinal Morbidity in Obesity

Abstract

Obesity is a complex disease that results from increased energy intake and decreased energy expenditure. The gastrointestinal system plays a key role in the pathogenesis of obesity and facilitates caloric imbalance. Changes in gastrointestinal hormones and the inhibition of mechanisms that curtail caloric intake result in weight gain. It is not clear if the gastrointestinal role in obesity is a cause or an effect of this disease. Obesity is often associated with type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). Obesity is also associated with gastrointestinal disorders, which are more frequent and present earlier than T2DM and CVD. Diseases such as gastro-esophageal reflux disease, cholelithiasis or non-alcoholic steatohepatitis are directly related to body weight and abdominal adiposity. Our objective is to assess the role of each gastrointestinal organ in obesity and the gastrointestinal morbidity resulting in those organs from effects of obesity.

Introduction

Obesity, defined as the excess of adipose tissue which results in a health risk, is usually associated with diabetes mellitus (T2DM) and cardiovascular disease (CVD). Gastrointestinal disorders resulting from obesity are more frequent and present earlier than T2DM and CVD. Hence, gastrointestinal morbidity in the obese person should be an alarm signal to address the excess adiposity more aggressively. Diseases such as gastroesophageal reflux disease (GERD), cholelithiasis, and non-alcoholic steatohepatitis are directly related to body weight and abdominal adiposity; they present earlier in the natural history of obesity. Raising awareness of these early conditions as complications of obesity and developing successful, low cost, safe interventions to reverse obesity could prevent the progression to T2DM and CVD.

The objective of this paper is to review each gastrointestinal organ in order to assess their potential role in obesity and the gastrointestinal morbidity associated with obesity.

The Role of Gastrointestinal Organs in the Pathophysiology of Obesity

Regulation of food intake is an essential factor in developing and maintaining obesity.¹ Gastrointestinal functions are, therefore, integral to obesity, as the stomach is the reservoir that determines entry of calories into the body, contributes to sensations of satiation or postprandial fullness, and signals the need to cease consumption of calories. Changes in gastric functions, such as more rapid gastric emptying or greater gastric accommodation, could lead to the ingestion of more calories, contributing to weight gain and obesity. Gastrointestinal hormones have an essential role in regulating appetite and satiety in coordination with the brain gut axis. Emerging evidence suggests that the microbiome within the gastrointestinal tract may have a role in obesity.

Satiation

The control of food intake has three stages: appetite, satiation and satiety. Appetite describes the desire for food; satiation is the sense of feeling full during a meal, which induces meal termination; in contrast, satiety is the degree of fullness or satiation prior to the consumption of the next meal. Gastric function influences all three stages in the control of food intake and merges the signals from mechanical receptors of the stomach and gastrointestinal hormones released in response to the contact of nutrients with taste receptors and enteroendocrine signalling in the gut, as well as the autonomic and enteric nervous systems. Thus, alterations in gastric function or in any of these mechanisms may alter the response to food intake and lead to caloric overconsumption.

The initial studies of gastric function and sensation are almost a century old and involved distending a balloon in the stomach and noting the feeling of fullness.^2-4 More recent studies use noninvasive measurement of gastric volumes to assess the association between abnormal gastric function and obesity or induction of postprandial symptoms. Delgado-Aros et al. showed that, across a broad spectrum of BMI, there was an association between higher BMI, higher fasting gastric volume, and decreased satiation. The decreased satiation was manifested as reduced symptoms of fullness, and a higher maximum tolerated volume of a nutrient drink ingested at a constant rate in a laboratory setting.^{5, 6} Figure 1 shows the higher maximum tolerated volume in obese compared to normal or underweight participants; an increase of 50mL in the fasting gastric volume was associated with 114±32kcal (479±134kJ) more ingested at maximum satiation.⁵ These findings suggest that individuals with a higher BMI require more food to reach satiation (and by inference, signal the need to terminate meal ingestion), and, over time, this results in higher caloric intake and weight gain. However, other data support the importance of behavioral adaptation; thus, other studies show obese individuals have more severe symptoms of fullness, bloating, nausea, pain when reaching maximal satiation than individuals without obesity, and yet they continue to ingest calories.^{1, 5, 7-9} This observation suggests that obese individuals can overcome the “stop” signal associated with satiation, and these data are consistent with a behavioral adaptation to satiation.¹⁰ Further studies are needed to differentiate the roles of stomach, the brain centers and the brain-gut axis in satiation and calorie overconsumption.

Figure 1.

Caloric intake at maximum satiation by gender and BMI. There was higher caloric intake at maximum satiation in male subjects compared with women (left). After adjusting for differences in sex, overweight (BMI 25–30 kg/m²) and obese (BMI>30 kg/m²) (merged as “obese”) showed higher caloric intakes at maximum satiation compared with normal weight subjects, whereas underweight individuals showed lower caloric intakes. Reproduced from Delgado-Aros et al. Gastroenterology 2004;126:432–440.

Appetite and Satiety

There are multiple mechanisms that decrease satiety and increase appetite in obesity. These include: gastric motor and sensory functions;¹¹ production of the appetite –promoting acyl ghrelin by the P/D1 cells of the stomach fundus;^{12, 13} a blunted response of the afferent vagus nerve to ingestion of a meal; and impaired release of other gastrointestinal hormones such as CCK, obestatin, GLP-1 or PYY, which usually inhibit gastric emptying and contribute to reduced appetite.^14-16

These pathophysiological changes in obesity are well characterized in animal models; however, in humans these findings have not always been consistent, as illustrated in the case of gastric emptying which may be slow, normal or fast in different studies.^{17, 18} Nonetheless, the most prevalent gastric dysfunction in obese subjects (when compared to lean controls) is rapid gastric empting of solids.^19-25 High fat diets retard gastric emptying. However, the alteration in gastric emptying in obesity does not appear to be related to the choice of macronutrient. Different types of high, but equicaloric diets (high fat, high protein, high carbohydrate or balanced nutrient content) do not differentially affect gastric emptying or gastric volume in humans.²⁶

Several signaling molecules and pathways involved in the control of food intake and obesity are associated with changes in gastric function (Table 1).^27-31 The potential role of these signaling mechanisms in the development of obesity is also illustrated by the effects of genetic variations in the control of the ligand or its receptor, the effect of obesity on the signaling mechanism, and the potential therapeutic effects of pharmacological doses of the gut hormone or peptide (Table 1).

Table 1.

Signaling molecules and pathways involved in control of food intake and obesity and their effects on gastrointestinal functions and food intake

Gastrointestinal hormone	Effect		Role in Obesity
	Gastric or SB function	Brain	Effect of Genetic variations	Changes due to obesity	Effect of Therapeutic doses
Acyl-Ghrelin	Accelerate GE, decreased GA	Increase Appetite	SNPs associated with obesity	Increased level of Acyl-ghrelin	Induces appetite and increases food intake
Obestatin	Delayed GE	Decreases appetite	SNP associated decrease in food intake	Decrease level of obestatin	Unknown
Cholecystokinin	Delayed GE, Decrease antral motility increases GA	Induce Satiation	SNPs associated with increase meal size	Decreased vagal response to CCK	Decreases food intake
Pancreatic Polypeptide	Delayed GE	Decrease Appetite	unknown	unknown	Decreases food intake
Glucose-dependent insulinotropic polypeptide (GIP)	Decreases gastric acid secretion	Increases appetite and food intake	SNPs associated with obesity	Increase level of GIP in obesity	Antagonists in preclinical trials
Glucagon-like peptide 1 (GLP-1)	Delayed GE, Increase GA	Increase satiation and satiety	GLP-1R SNPs associated with altered beta-cell responsivity to GLP-1	Decreased in obese T2DM	Induces weight loss and glycemic improvement
Oxyntomodulin	Delayed GE	Increase Satiety	unknown	unknown	Decreases FI and induces weight loss
Peptide YY	Delayed GE; mediator of ileal brake	Increase Satiety	SNPs associated with obesity	Decreased in obesity in some studies	Induces weight loss
FGF-19	No effect	Increase satiety	unknown	Decreased in obesity	Unknown

FGF-19= fibroblast growth factor-19; GE= gastric accommodation; GE=gastric emptying; SNP=single nucleotide polymorphism;

At present, the lipase inhibitor, orlistat, and most of the medications [e.g. sibutramine,²⁹ GLP-1 agonists,³² pancreatic polypeptide,³³ fenfluramine-phentermine,^{34, 35} peptide YY_(3-36)] to induce weight loss produce effects on the gut, such as fat malabsorption, a delay in gastric emptying, as well as other effects.^{36, 37} It is still unclear whether obesity medications affect gastric capacitance or satiation, with the exception of sibutramine which caused significant retardation in gastric emptying of solids, reduced maximum tolerated volume (increased satiation), and increased postprandial peptide YY, but did not affect gastric capacity, compared with placebo.²⁹

Gut Hormones and Calorie Consumption

The small intestine is the site of digestion and absorption of most nutrients; alterations in the normal physiology of the small intestine allow an overconsumption of calories. Examples of these alterations are: first, individuals with mutated small intestinal hormones, e.g. genetic polymorphisms of PYY gene, tend to become obese;³⁸ second, obese individuals have lower concentrations of small intestinal hormones, such as CCK,³⁹ GLP-1,^{16, 40} OXM,⁴¹ and FGF-19⁴² (Table 1); third, obese individuals with insulin resistance may have an increase in small intestinal enterocyte mass when compared to obese individuals without insulin resistance.^{43, 44}

Gut-Brain Axis

Energy balance is a complex mechanism in which the gastrointestinal and central nervous systems are tightly connected (review in detailed elsewhere).⁴⁵ Orexigenic gastrointestinal hormones such as ghrelin activate the neuropeptide Y/agouti related peptide (NPY/AGRP) appetite pathway in the arcuate nucleus of the hypothalamus, and anorexigenic gastrointestinal hormones such as GLP-1 or PYY3-36 inhibit the NPY/AGRP and stimulate the proopiomelanocortin/cocaine-amphetamine related transcript (POMC/CART) pathway in the arcuate nucleus of the hypothalamus to induce satiation and satiety and stop food intake. The arcuate nucleus sends signals to the paraventricular nucleus and the lateral hypothalamic area. In the brainstem, orexigenic and anorexigenic gut hormones modulate the nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of vagus (DMNV) and convey signals to the hypothalamus and higher brain areas. The effects on the hypothalamus and brainstem trigger higher brain area responses, modulating behavior (e.g. initiating or stopping eating) and enhancing nutrient-related reward. ⁴⁵

Microbiome

Emerging evidence suggests interaction of the human gut microbiome with metabolic and gastrointestinal systems.^46-48 Gut bacteria are essential in deconjugation, dehydrogenation, and dehydroxylation of primary bile acids in the distal small intestine and colon.⁴⁹ The microbiota contribute to breaking down otherwise indigestible carbohydrates and increasing short chain fatty acid absorption in the colon, providing additional energy and increasing fat storage in adipose tissue.^{46, 47} The microbiota in obese subjects appear to be different from those of lean subjects.⁴⁸

Gastrointesinal Morbidity in Obesity

Obesity is a state of low-grade chronic inflammation that affects the whole body including the gastrointestinal organs. ⁵⁰ Compared to people of lean body weight, the overweight or obese phenotype is associated with increased tissue inflammatory cytokines, activated immune responses and altered cell signalling of metabolic pathways. ^51,52 In general, low-grade chronic inflammation and changes in metabolic hormones and the distribution of the adipose tissue in the abdominal cavity in obesity participate in development of gastrointestinal morbidity.

Esophagus

Many esophageal disorders are related to obesity. The excess of body weight, especially increase in the abdominal girth, produces a higher intra-abdominal pressure and higher gastric acid production, reduces lower esophageal sphincter pressure, reduces the intra-abdominal length of the lower esophageal sphincter, and induces esophageal motor dysfunction.^{53, 54} Independent of abdominal waist circumference, obesity is also associated with increased acid exposure.^{54, 55} The mechanism of obesity-related hyperacidity may be based on increased estrogen levels compared to age and gender adjusted normal weight individuals. Increased estrogen levels are strongly associated with increased acid exposure and GERD, the association is stronger in women than in men.^56-58 These pathophysiological changes can produce regurgitation, esophagitis and GERD, which can progress to Barrett’s esophagus and esophageal adenocarcinoma.

Gastroesophageal Reflux Disease

GERD is a chronic disorder characterized by the symptoms of heartburn and regurgitation that occur when gastric acid or bile reflux from the stomach to the esophagus. The gastric refluxate produces inflammation of the lining of the esophagus. The prevalence of GERD has increased significantly in the last 15 years, in parallel with the increased prevalence of obesity. Two meta-analyses have shown a positive association between body weight (BMI) and GERD.^{59, 60} The association of BMI and GERD is stronger in obese women than in obese men; this difference has been attributed to increased estrogen levels in women.⁵⁷ The association of BMI and GERD is stronger in Caucasians than in other ethnicities.⁶¹ The strong association between obesity and GERD is reinforced by improvement of GERD symptoms after weight loss.⁶² The American College of Gastroenterology, therefore, recommends weight loss to patients with GERD who are overweight/obese or recently gained weight.⁶³

Erosive Esophagitis

Erosive esophagitis is the inflammation of the mucosa of the esophagus secondary to gastroesophageal reflux disease. The risk factors for developing erosive esophagitis are male gender, older age, chronic alcohol intake, chronic smoking, increased BMI, and long history of GERD.⁶⁴ Several meta-analyses have demonstrated the association of a higher BMI, increased waist circumference and/or increased waist to hip ratio with erosive esophagitis and its severity.^{60, 65, 66} Patients with central adiposity have a 1.87 higher risk of developing erosive esophagitis compared to normal weight controls, and this effect of central adiposity (orange shape) is independent of body weight (OR, 1.87; 95% CI, 1.51–2.31).⁶⁶ In contrast, the increase in hip circumference or gluteofemoral (pear-shaped) obesity is inversely related to erosive esophagitis and Barrett’s esophagus. These findings show that gluteofemoral obesity has a protective role in developing erosive esophageal disease in addition to being protective for progression to T2DM and CVD.⁶⁷

Barrett’s Esophagus

Barrett’s esophagus describes metaplasia in which the normal squamous cell epithelium of the distal esophagus is replaced by a specialized columnar epithelium. Barrett’s esophagus is usually a consequence of chronic GERD⁶⁸ and predisposes to adenocarcinoma of the esophagus.^69-71 As with GERD and erosive esophagitis, multiple studies have shown an association between obesity, abdominal circumference and metabolic syndrome with Barrett’s esophagus.^{68, 70, 72} Subsequent meta-analyses have shown that BMI and abdominal adiposity (measured by waist circumference) may be indirect risk factors for Barrett’s esophagus due to the relation with GERD.⁷³ The association of Barrett’s esophagus with abdominal adiposity is even stronger when adjusted for BMI or GERD, suggesting that abdominal adiposity is an independent risk factor to developing Barrett’s esophagus.⁶⁶ The mechanism for the independent association of abdominal adiposity with Barrett’s esophagus may be explained by higher levels of leptin, decreased levels of low molecular weight adiponectin, and increased cytokines which mediate chronic inflammation.^74-76 Although these mechanisms are not specific for abdominal obesity, further studies are needed to understand the independent association of abdominal adiposity with Barrett’s esophagus.

Esophageal Adenocarcinoma

Esophageal adenocarcinoma incidence rates are rising dramatically and it is considered likely due to the increased prevalence of Barrett’s esophagus, erosive esophagitis and GERD. These conditions are all associated with obesity and abdominal adiposity. In subjects with Barrett’s esophagus, obesity is directly associated with progression to adenocarcinoma, suggesting that obesity may at least modify the risk to develop adenocarcinoma. Higher levels of leptin and lower levels of adiponectin have been proposed as markers of progression to adenocarcinoma.⁷⁷ In a meta-analysis of 2488 cases of esophageal adenocarcinoma, there was a strong association with obesity (males: OR 2.4, 95% CI: 1.9–3.2) and (females: OR 2.1, 95% CI: 1.4–3.2).⁷⁸ In another meta-analysis, there was significantly higher risk of esophageal adenocarcinoma with increased central adiposity (OR, 2.51; 95% CI, 1.56–4.04) when compared to normal body habitus.⁶⁶

Many molecular pathways link obesity, metabolic syndrome and cancer. First, increased insulin and insulin-like growth factor (IGF) might provide a mechanistic link between obesity and esophageal adenocarcinoma.^{79, 80} Second, IGF-1 and IGF-2 increase angiogenesis and cell proliferation, and decrease apoptosis. Third, elevated cytokines secondary to obesity-induced chronic inflammation induce vascular endothelial growth factor (VEGF), decrease adiponectin and increase leptin (Figure 1).⁷⁶ Leptin stimulates cell proliferation by activating epidermal growth factor receptor (EGFR)and inhibits apoptosis in esophageal cells.⁸¹ Histopathological studies of esophageal adenocarcinoma from obese patients have shown upregulated expression of leptin and adiponectin receptors in the esophageal tumor.⁸²

Esophageal Dysmotility

Obesity increases the prevalence of esophageal motility disorders. In one study, esophageal transit time was significantly prolonged in obese subjects compared to lean subjects.⁸³ The increased esophageal transit time is considered to be a consequence of increased gastric and gastroesophageal junction resistance.⁸⁴ In two cohorts of 111 and 116 obese patients who underwent esophageal manometric studies prior to surgery, 61% of patients had typically non-specific manometric abnormalities of esophageal peristalsis and a wide range of lower esophageal sphincter (LES) dysfunction, including isolated hypertensive LES pressure (>35mmHg, 3-14%), isolated hypotensive LES pressure (<12mmHg, 3%), diffuse esophageal spasm (1-7%), and achalasia (1%).^{85, 86} However, the specificity and significance of these findings are unclear in the absence of lean control studies.

Stomach

While obesity alters the gastric physiology and its neuro-hormonal-enteric regulation,¹⁷ it is unclear whether gastric function abnormalities are the cause or consequence of obesity. Obesity is associated with symptoms that may arise in the stomach, such as upper abdominal pain, nausea, vomiting, retching, and gastritis.^{87, 88}

Erosive Gastritis

Erosive gastritis, similar to erosive esophagitis, is an endoscopic and histological diagnosis defined as inflammation in the mucosa of the stomach. Gastritis could be acute or chronic and can lead to ulceration and bleeding. Obesity is a risk factor for erosive gastritis and gastric and duodenal ulcer.^{89, 90} Yamamoto et al. suggested that there is an association of low adiponectin with erosive gastritis, independent of BMI or H. pylori infection.⁹¹ Adiponectin is reduced in abdominal obesity and metabolic syndrome and is the mediator of co-morbidities related to obesity.⁹²

Gastric Cancer

Obesity is considered a pro-inflammatory and pro-carcinogenic state and is becoming one of the most important, modifiable risk factors for cancer, including gastric cancer. The association of gastric cancer and obesity was summarized in a meta-analysis which showed that excess BMI was associated with increased risk of gastric cancer.⁹³ A subsequent larger meta-analysis found obesity was associated mainly with an increased risk of gastric cardia cancer.⁹⁴ It is not clear if the association is related to other confounders such as an association of obesity with H. pylori infection.⁹⁵ There are data supporting the concept that obesity accelerates H.pylori mediated gastric carcinogenesis.⁹⁶

Small Intestine

The small intestine is the site of digestion and absorption of most nutrients. As with the stomach, the small intestine adapts to caloric overconsumption; in addition, alterations in the normal physiology of the small intestine allow an overconsumption of calories.

Diarrhea

The prevalence of diarrhea is higher in obese patients when compare to normal weight controls.⁹⁷ A population-based survey study in Rochester, MN of 2,660 people showed that the prevalence of diarrhea in obese individuals was 30% compared to 17% in normal weight controls [OR = 2.7 (95% CI 1.1–6.8)].⁸⁸ Similar studies have been replicated in Australia and New Zealand.^{98, 99} The higher prevalence of diarrhea could be attributed to changes in bile acids, resulting in bile acid diarrhea,¹⁰⁰ due to increased colonic transit¹⁰¹ and/or due to increased permeability.^{102, 103} Obesity is also associated with increased levels of fecal calprotectin, a marker of intestinal inflammation. ¹⁰⁴ Medications used by obese individuals, such as metformin for T2DM or polycystic ovary syndrome, may also cause diarrhea.¹⁰⁵

Celiac Disease

Celiac disease is an immune disease in response to gluten and mainly affects the small intestine. The typical presentation is weight loss, diarrhea and malabsorption. Paradoxically, the recognition and prevalence of celiac disease in the obese population are increasing. In patients with newly diagnosed celiac disease, the prevalence of obesity varies from 39 to 44%.^{106, 107} Obese patients with celiac disease are more likely to gain more weight on a gluten-free diet.^{106, 108} Similar finding are reported in children with celiac disease.¹⁰⁹

Inflammatory Bowel Disease

Inflammatory bowel diseases (IBD) –Crohn’s disease or ulcerative colitis – are autoimmune disorders which mainly target the small bowel and colon. In a case control study, there was a U-shaped association between BMI and Crohn’s disease. Patients who are underweight or overweight are more likely to have Crohn’s disease.¹¹⁰ These findings were not reproduced in a recent European cohort which showed no association between obesity and IBD in adults.¹¹¹ On the contrary, in children, the prevalence of obesity in IBD is similar to that in the general population, but obese children with IBD have a more severe disease than those of normal weight.¹¹²

Colon and Rectum

Constipation

The association between obesity and constipation is controversial. Delgado-Aros et al. showed that the prevalence of constipation is higher in obese people in a community-based epidemiological study;⁸⁸ these findings were not reproduced in other large cohort studies.⁹⁹ In children, constipation, but not constipation-predominant irritable bowel syndrome, is more common in obese individuals.^{113, 114}

Diverticular Disease

Diverticulosis and diverticulitis are more common in the colon with aging. Obesity is associated with a higher risk of developing diverticulosis¹¹⁵ and with more diverticular bleeding and recurrent diverticulitis than normal weight individuals.¹¹⁶

Colonic Polyps

There are three main types of polyps in the colon: adenomas, serrated, and hyperplastic. Adenomas and serrated polyps predispose to colon cancer. Several studies have documented the increased prevalence of adenomatous polyps with higher BMI (OR 2.1, 95% CI 1.4-2.3)¹¹⁷ or obesity (OR 2.16, 95% CI 1.13-4.14). This association was stronger in women (OR 4.42; 95% CI 1.53-12.78) than in men (OR 1.26, 95% CI 0.52-3.07). The study also found that weight gain is another risk factor for adenomas (OR 2.30, 95% CI, 1.25-4.22).¹¹⁸ The association of higher BMI and colonic adenomatous polyps has been validated in other cohorts and populations.^119-123 Similarly, obesity is associated with an increased risk of adenoma recurrence.¹²⁴ Obesity is also associated higher risk of sessile serrated polyps of the colon (OR 2.57, 95% CI 1.75-4.90), with even stronger association if the serrated polyp is larger than 1cm (OR 3.96, 95% CI 1.27-12.36).¹²⁵

Colorectal Cancer

Colorectal cancer is the fourth most common cancer in the United States. The incidence of colon cancer is similar in men and women and increases with age; 90% of cases of colorectal cancer occurs after age 50. Multiple meta-analyses in over 70,000 cases of colon cancer show obesity as a risk factor.^126-129 For every increase in BMI of 5kg/m², the risk of colon cancer increases by 18%.¹²⁷ The association of obesity and colorectal cancer is stronger in men than in women (RR 1.24, 95% CI 1.20–1.28 for men, and RR 1.09, 95% CI 1.04–1.12 for women).¹²⁶ The risk of colorectal cancer increases with a higher waist circumference (RR 1.33, 95% CI 1.19-1.49 for men, and RR 1.16, 95% CI 1.09-1.23 for women).¹²⁹ The relationship of obesity, abdominal adiposity and colon cancer is likely to be multifactorial due to changes in leptin, adiponectin, the microbiome, secondary bile acids, and insulin resistance, and has been extensively reviewed elsewhere.¹³⁰

Anal Canal and Pelvic Floor

Dyssynergic Defecation

Female patients have a higher likelihood of experiencing constipation secondary to pelvic floor disorders (83% in one large series of 390 female patients ¹³¹ and, particularly, constipation associated with descending perineum syndrome, ¹³² which is usually associated with multiparity and is almost exclusively observed in females. However, it is unclear whether BMI is an independent risk factor in constipation associated with these pelvic floor disorders.

Fecal Incontinence

Fecal incontinence, defined as the inability to control bowel movements, producing undesired leakage of stool from the rectum, has been associated with a higher BMI, but the association has been weak or not statistically significant. Studies report a range of results from no association to up to 69% of obese subjects having fecal incontinence.^{87, 133}

Liver

It has been proposed that, in the western world, obesity and non-alcoholic fatty liver disease (NAFLD) will be leading risk factors for cirrhosis in the next decade, especially because of the recent advances in treatment of viral hepatitis and the increasing epidemic of obesity. Additionally, NAFLD is strongly associated with metabolic syndrome, cardiovascular disease and diabetes mellitus type 2, as the liver is an essential organ in the regulation of digestion, energy distribution, and fat storage, and the latter may lead to lipotoxicity which may be the mechanism for development of metabolic syndrome, insulin resistance and diabetes.

Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease is the accumulation of fat in the liver in the absence of other possible causes such as alcohol. Obesity contributes to the accumulation of lipid in the liver by increasing uptake of free fatty acids into the liver, impairing fatty acid beta oxidation, or the increasing incidence of de novo lipogenesis. ¹³⁴ NAFLD is subclassified into non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). The main difference between NAFL and NASH is the degree of hepatic inflammation, which may be indistinguishable from alcoholic steatohepatitis. The worldwide prevalence of NAFLD is 20% (range 6 to 35%) and, in the USA, the prevalence range is from 10 to 46%. The prevalence of NAFLD in obese adults is as high as 90 to 95% and, in diabetics, it is up to 70%. ¹³⁵ Obese persons have up to 4.6 times higher risk (95% CI, 2.5 - 110) of developing hepatic steatosis compared to lean controls. ¹³⁶ Around 20% of patients with NAFLD will progress to NASH, and 20% of those with NASH will end up having cirrhosis. ¹³⁷ NAFLD is currently the third most common cause of hepatocellular carcinoma (HCC) in the USA, after viral hepatitis and alcoholic cirrhosis. ¹³⁸ It is intriguing that one-third of the cases of HCC occurred in the absence of NAFLD-associated cirrhosis. ^{138, 139} There was a strong association between obesity (adjusted HR, 4.1; 95% CI, 1.4–11.4) or being overweight (adjusted HR, 1.93; 95% CI, 0.7–5.3) and cirrhosis-related death or hospitalization.¹⁴⁰

Treatment of NAFLD is based initially on weight loss and physical activity: “Loss of at least 3-5% of body weight appears necessary to improve steatosis, but a greater weight loss (up to 10%) may be needed to improve necroinflammation (Strength – 1, Evidence - B).”¹⁴¹

Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide. ¹⁴² Obesity, possibly due to associated low-grade chronic inflammation, has been associated with the risk of all cancer, including HCC. ¹⁴³ Case–control and cohort studies concluded that the relative risk (RR) of HCC was 1.17 (95% confidence interval (CI): 1.02-1.34) for overweight¹⁴⁴ and 1.89 (95% CI: 1.51-2.36) for obese patients. ¹⁴⁵ Furthermore, abdominal obesity was associated with 3.51 increase in RR for HCC (95% CI: 2.09–5.87),¹⁴⁶ and general obesity was an independently significant risk factor. ¹⁴⁷ The effect of obesity on HCC is likely due, in part, to NAFLD and low-grade inflammation per se. ¹⁴⁸ Additionally, obese patients with HCC have a poor prognosis when compared to non-obese group.¹⁴⁹

Gallbladder

Obesity has been well recognized for its strong association with gallstones diseases. ^{150, 151} Obese subjects have a higher incidence of cholelithiasis, cholecystitis and cholesterolosis when compare to lean controls.¹⁵² A meta-analysis showed that the risk for gallbladder disease in men was 1.63 [95% CI: 1.42–1.88] for overweight and 2.51 [95% CI: 2.16–2.91] for obesity; in women, the RR was 1.44 [95% CI: 1.05–1.98] for overweight and 2.32 [95% CI: 1.17–4.57] for obesity.¹⁵³ Abdominal circumference is a risk factor for gallstones diseases, independent of BMI. ^{154, 155} These associations have been attributed to abdominal adiposity, hyperinsulinemia, insulin resistance, hyperleptinemia, hyperlipidemia and gallbladder dysmotility. ^{150, 156-158}

Pancreas

Obesity and fat infiltration of the pancreas play a significant role in the endocrine pancreatic dysfunction that leads to the development of type 2 diabetes mellitus (further details are not pertinent for this review) ¹⁵⁹. Obesity has also been associated with pancreatitis and pancreatic cancer.

Acute pancreatitis

Acute pancreatitis is defined as inflammation of the pancreas and can be mild to fulminant, with mortality up to 20% in severe necrotizing pancreatitis.^{160, 161} In a meta-analysis, obese subjects had an increased risk of developing severe acute pancreatitis (RR=2.20, 95% CI 1.82–2.66), higher risk of local (RR=2.68, 95% CI 2.09–3.43) and systemic complications (RR=2.14, 95% CI 1.42–3.21), and higher risk of in-hospital mortality (RR=2.59, 95% CI 1.66–4.03) when compared to lean subjects, ¹⁶¹ These associations have been attributed to low-grade chronic inflammation, and low levels of adiponectin. ^{144, 162, 163}

Pancreatic cancer

Pancreatic cancer is the ninth most common cause of cancer worldwide. ¹⁶⁴ Multiple meta-analyses have reported an association between BMI as well as abdominal obesity with occurrence of adenocarcinoma of the pancreas. A recent meta-analysis showed a 10% increased risk in women and 13% increased risk in men for every 5 units higher BMI (95% CI 1.04–1.22).¹⁶⁵ Additionally, for every extra 10cm of waist circumference, there was an 11% increased risk of pancreatic cancer (RR=1.11, 95% CI: 1.05–1.18).¹⁶⁵

Summary

Table 2 summarizes the quantified risks of gastrointestinal disorders in obesity. The increased prevalence of gastrointestinal morbidity in the general population may be related to the increased prevalence of obesity in western countries. Thus, it is important to recognize the role of higher BMI and, particularly, increased abdominal adiposity in the development of gastrointestinal morbidity, which sometimes are neglected because of the effects of obesity on diabetes mellitus and cardiovascular disease that deservedly demand the physician’s attention.

Table 2.

Quantified risk ratios of gastrointestinal disorders in obesity

Gastrointestinal Disease	Obesity as risk factor		Reference
	Risk (OR or RR)	Confidence Interval
Esophagus
Gastro-Esophageal Reflux Disease (GERD)	OR = 1.94	95%CI, 1.46-2.57	60
Erosive Esophagitis	OR = 1.87	95% CI, 1.51-2.31	66
Barrett Esophagus	OR = 4.0	95% CI, 1.4-11.1	68
Esophageal Adenocarcinoma	Men: OR = 2.4 Women: OR = 2.1	95% CI: 1.9–3.2 95% CI: 1.4–3.2	78
Stomach
Erosive Gastritis	OR = 2.23	95% CI, 1.59-3.11	90
Gastric Cancer	OR = 1.55	95% CI, 1.31-1.84	93
Small intestine
Diarrhea	OR = 2.7	95% CI, 1.10-6.8	88
Colon and rectum
Diverticular disease	RR = 1.78	95% CI, 1.08-2.94	116
Polyps	OR = 1.44	95 % CI, 1.23-1.70	166
Colorectal Cancer	Men: RR = 1.95 Women: RR=1.15	95% CI, 1.59-2.39 95% CI, 1.06-1.24	130
Liver
NAFLD	RR = 4.6	95% CI, 2.5-110	136
Cirrhosis	RR = 4.1	95% CI, 1.4–11.4	140
Hepatocellular carcinoma	RR = 1.89	95% CI: 1.51-2.36	145
Gallbladder
Gallstones disease	Men: RR = 2.51 Women: RR=2.32	95% CI, 2.16–2.91 95% CI, 1.17–4.57	153
Pancreas
Acute pancreatitis	RR = 2.20,	95% CI 1.82–2.66	161
Pancreatic cancer	Men: RR = 1.10 Women: RR=1.13	95% CI, 1.04–1.22 95% CI, 1.05–1.18	165

Conclusion

In conclusion, gastrointestinal disorders are directly caused by obesity, although understanding the association of obesity and gastrointestinal morbidity is limited by the lack of studies analyzing the effects of weight loss as potential therapy or risk reduction in gastrointestinal morbidity; for example, it is unclear whether there is resolution of GERD or chronic diarrhea after significant non-surgical weight loss in obese patients. Furthermore, the gastrointestinal system plays an essential role in the development of obesity through its modulation of appetite, satiation and satiety. The role of the gastrointestinal tract is emphasized by the observation that the most effective treatment for obesity is bariatric surgery, which alters the gastrointestinal anatomy and causes metabolic adaptations to energy intake.

Figure 2.

Body mass index in men and women with idiopathic bile acid malabsorption and in healthy men and women shown as median, IQR, and percentile 10 and 90. The dashed line shows the upper limit of normal weight (25kg/m²). Reproduced from Sadik et al. Am J Gastroenterol 2004;99:711-718.