CONFLUENCE OF EPIDEMICS

There have been two recent and concomitant epidemics: one in GORD and its complications, and the other in obesity.

The prevalence of GORD and related disorders has been steadily increasing in the US and western Europe, Scandavian countries and Australia.1 While improved detection and awareness may partly explain the observed trends, a true increase in GORD incidence is likely. This increase is relatively easily demonstrated for acute disabling conditions such as oesophageal adenocarcinoma,2 and less obvious for chronic (e.g. GORD symptoms3) or asymptomatic lesions (e.g. Barrett’s oesophagus).4 5

Obesity, typically defined as a body mass index (BMI) of >30, has risen in epidemic proportions in several regions in North America, Europe and Asia. The United States leads the way in this regard where, since the mid-1970s, the prevalence of overweight and obesity has increased sharply for both adults and children. For example, data from two NHANES surveys show that among adults aged 20–74 years the prevalence of obesity increased from 15.0% (1976–1980) to 32.9% (2003–2004).6 7 Increased food availability, larger serving size, increased fattening dietary items, and decreased physical activity has been blamed for the observed trends.

The confluence between the gastroesophageal reflux disease (GORD) related disorders (symptoms, oesophageal erosions, Barrett’s oesophagus, and oesophageal adenocarcinoma) and the obesity epidemics has generated great interest in the association between these two conditions and the potential mechanisms to explain this association.

ASSOCIATION BETWEEN OBESITY AND GORD-RELATED DISORDERS

We conducted a systematic review and meta-analysis of epidemiological studies that examined the association between obesity and several GORD-related disorders (symptoms, oesophageal erosions, oesophageal adenocarcinoma).8 As of 2005, we identified 23 relevant studies: nine for GORD symptoms, seven for erosive oesophagitis, and seven studies for oesophageal adenocarcinoma. These studies were mostly conducted in countries from North America or western Europe. Obesity was associated with a significant 1.5- to 2-fold increase in the risk of GORD symptoms and erosive oesophagitis, and a 2- to 2.5-fold increase in the risk of oesophageal adenocarcinoma as compared to individuals with normal BMI. There was also some degree of dose-dependent relationship between BMI and these GORD-related disorders. Subsequent meta-analyses has confirmed these findings in a larger number of studies from the US and highlighted the heterogeneous results from Europe with individual studies demonstrating both positive associations and no association.9 10 In addition, a recent large cohort study in women reported a possible dose–response increase in the risk of GORD with higher BMI even in the normal range of BMI.11

During the past 2 years, several studies examined the association between obesity and Barrett’s oesophagus and arrived at mixed results from a significant risk increase with high BMI,12 13 significant increase with high BMI only in the presence of GORD symptoms,14 or no association.15 Two large case–control studies in the US reported that abdominal diameter but not BMI was an independent risk factor of Barrett’s oesophagus.

The association between obesity and GORD symptoms has been examined in high-quality studies that examined GORD symptoms using validated questionnaires in randomly selected samples of the general population; however, the strength of the association is rather modest and three16^–18 studies showed no significant association. On the other hand, the studies on oesophageal erosions and Barrett’s oesophagus are mostly from clinic-based studies and are therefore susceptible to ascertainment bias. Five out of these six studies that examined erosive oesophagitis, including one cohort study,19 showed a significant positive association with obesity, while only one study that was conducted in Japan showed no significant association.20 For oesophageal adenocarcinoma, the association with obesity is most pronounced, and comes from population-based case–control studies. Recall bias is a major problem in cancer studies. For example, if patients with cancer were concerned that their eating habits and BMI may have caused their disease process, they were more likely to overestimate their historical weight compared to non-cancer controls. However, several cancer studies had a control group of either squamous cell cancer of the oesophagus or distal gastric adenocarcinoma, and BMI was found to have either no association or a significant negative association with these cancer controls21 22 thus arguing against recall bias.

Diet and physical activity

The effects of obesity could be confounded by dietary intake and physical activity. It has also been postulated that consumption of fatty foods, rather than obesity is responsible for GORD.23 With the exception of oesophageal adenocarcinoma, large-scale epidemiological studies evaluating detailed dietary factors are sparse. In these studies, the effect of BMI seems to be independent of total caloric intake, dietary intake of fibre, fruits and vegetables, or other macronutrients or micronutrients.21 24 25 The uncertainty about the relevant exposure period in the life of patients with GORD-related disorders coupled with difficulty in accurate measurement of dietary intake especially during remote times has contributed to the difficulty in conducting and interpreting dietary studies. The role of physical activity has not been adequately examined.

In summary, a causal association between obesity and GORD-related disorders is suggested by the parallel secular trends, the consistent significant association in most cross-sectional and case–control studies, the compatible temporal association in cohort studies, and the suggestive dose–response relation.

CAN OBESITY EXPLAIN THE EPIDEMIOLOGICAL FEATURES OF GORD-RELATED DISORDERS?

There are gender and race/ethnicity-related differences in the distribution of GORD. GORD symptoms seem to be equally prevalent between men and women, and between Caucasians and other racial/ethnic groups, oesophagitis is more common among men and Caucasians,26 Barrett’s oesophagus is much more common in men and Caucasians (70–80%),27 while oesophageal adenocarcinoma is dominated by men and Caucasians.2 Simple obesity does not better explain gender or ethnic predilections because the prevalence of obesity is also increasing rapidly in demographic groups at relatively low risk of Barrett’s oesophagus and oesophageal adenocarcinoma (e.g. women and African Americans). There has been recent interest in the possible role of abdominal obesity in GORD-related disorders. Abdominal obesity better explains some of the epidemiological features of Barrett’s oesophagus and oesophageal adenocarcinoma. The distribution of body fat tends to be more visceral than truncal in high-risk groups for Barrett’s oesophagus including Caucasians (compared with African Americans), and men (compared with women).28 A recent study reported a consistent association between abdominal diameter (independent of BMI) and GORD symptoms in whites, but not in blacks or Asians.29 These findings, combined with the increased prevalence of abdominal obesity in males, suggest that increased obesity may disproportionately increase GORD in whites and in males. Two other recent studies have shown abdominal diameter measured as waist circumference to be a risk factor of Barrett’s oesophagus independent of BMI, while the association between BMI and Barrett’s oesophagus disappeared after adjustment of abdominal diameter.30 31 These studies indicate that abdominal fat is the key factor linking obesity and Barrett’s oesophagus.

MECHANISMS BY WHICH OBESITY MAY CAUSE GORD-RELATED DISORDERS

Mechanical disruption of OGJ

The leading hypothesis is that abdominal obesity promotes gastroesophageal reflux through increased pressure stress and anatomical disruption of the gastroesophageal junction. Obese individuals may experience extrinsic gastric compression by surrounding adipose tissue leading to increasing intragastric pressures, and subsequent relaxation of the lower oesophageal sphincter thus facilitating abnormal reflux (fig 1). Transient lower oesophageal sphincter relaxation (TLOSR) is the most important mechanism of reflux, and may be the only mechanism of reflux observed in patients with mild reflux. A recent study from China32 used combined 2 h postprandial oesophageal manometry and pH monitoring after a standard test meal to evaluate 28 obese (BMI >30) patients referred for weight reduction procedures and age- and sex-matched eight overweight (BMI 25–30) and 28 normal weight (BMI >20 and <25) subjects. Patients with reflux symptoms, treatment or hiatus hernia were excluded. During the postprandial period, both obese and overweight groups had a substantial increase in the 2 h rate of TLOSR and the proportion of TLOSR with acid reflux. Both BMI and waist circumference were significantly positively correlated with TLOSR and there was a dose–effect relationship. Therefore, it seems that higher postprandial intragastric pressure in abdominal obesity32^–34 leads to more intense stimulation on both stretch and tension mechanoreceptors in the proximal stomach, which provokes more postprandial TLOSRs.

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Figure 1 Obesity has been associated with increased intragastric pressure, gastroesophageal pressure gradient,34 transient relaxation of the lower oesophageal sphincter,32 and exposure to oesophageal acid.38 In panel A, the left three bars refer to the BMI, and the right three bars refer to the waist circumference. *p<0.05.

The anatomical disruption of the oesophagogastric junction (OGJ) would result in the formation of a hiatal hernia. A study of 285 patients34 analysed the relationship between obesity, pressure stresses on the OGJ, and the morphology of the OGJ pressure segment itself using a solid-state manometric assembly with 36 circumferential sensors spaced at 1 cm intervals. Intragastric pressure as well as the gastroesophageal pressure gradient during both expiration and inspiration was significantly higher in obese and overweight patients compared with those with a normal BMI. Waist circumference was an independent risk factor for increased intragastric pressure, whereas BMI was no longer significantly associated with pressure independent of waist. The associations were stronger in men than women. There was a dose–response relationship such that the higher the BMI and waist circumference, the greater the intragastric pressure and gastroesophageal pressure gradient. Obesity was also associated with increased axial separation between the lower oesophageal and the extrinsic crural diaphragm, an objective measure of the anatomical disruption of the OGJ culminating in the development of hiatal hernia. The support for this supposition is weak in epidemiological studies. One study found obesity to be significantly associated with oesophagitis35 only in the presence of hiatal hernia. Similarly, Stene-Larson et al36 found that 68% of patients with oesophagitis had concomitant hiatal hernia and that obesity was significantly associated with both conditions, and El-Serag et al37 found that obesity was a risk factor for severe oesophagitis independent of hiatal hernia. Conversely, Wu et al,18 found no significant association between BMI and hiatal hernia. In all of these studies, however, hiatus hernia was not identified and in those that did, the criteria for identifying and measuring hiatal hernia may not have been used correctly or uniformly.

The OGJ changes are hypothesised to increase reflux across the lower oesophageal sphincter with subsequent increased oesophageal exposure to gastroduodenal contents. We conducted a cross-sectional study of 206 consecutive patients undergoing 24 h pH-metry who were not on acid-suppressing medications.38 Both BMI >30 and high waist circumference were associated with a significant increase in acid reflux episodes, long reflux episodes (>5 min), time with pH<4, as well as a calculated summary score. The association between obesity and oesophageal acid exposure also became attenuated when adjusted for waist circumference suggesting that the latter may mediate a large part of the effect of obesity. The modest correlation between oesophageal acid exposure as measured by 24 h pH-metry and the presence of GORD symptoms39 may explain the apparently limited role of GORD symptoms in explaining the association between obesity and Barrett’s oesophagus or oesophageal adenocarcinoma in epidemiological studies.22 30

Inflammatory mediators

A second mechanism by which obesity can cause GORD relates to the visceral component of abdominal obesity. Visceral obesity has been associated with increased risk of several disorders such as diabetes, ischaemic heart disease, and malignancies including colorectal cancer. Visceral fat is metabolically active, and has been strongly associated with low serum levels of potentially protective (e.g. adiponectin), or proinflammatory cytokines (e.g. interleukin-1β, interleukin-6 and tumour necrosis factor-α). The latter two cytokines have been shown in multiple studies to be over-expressed in erosive oesophagitis and Barrett’s oesophagus,40 and may potentially increase the inflammation and hence the malignant transformation in patients with erosive oesophagitis and Barrett’s oesophagus. Our group conducted a case–control study in patients who underwent endoscopy at a single large VA Medical Center. Cases were 36 patients with documented Barrett’s oesophagus who had an abdominal computed tomography (CT) scan within 1 year of the endoscopy, whereas controls were 93 patients without Barrett’s oesophagus who also had an abdominal CT scan.12 The surface areas of visceral adipose tissue calculated from CT scan images at level of intervertebral disc between L4 and L5 was approximately 1.5-fold greater in cases than controls (183 v 115 cm2; p<0.0001), whereas differences in subcutaneous adipose tissue were less pronounced (248 v 200 cm2; p = 0.03). However, this study was limited by small sample size and selection bias. Despite its biological plausibility, this hypothesis has not been dirctly examined.

Oestrogen

Oestrogens may mediate the association between obesity and GORD in women. Two studies conducted by the same group of investigators from Sweden suggested that the association of obesity and GORD might be mediated by the effect of circulating oestrogen.41 42 The first study reported a significant association between obesity and oesophagitis in women, and that the use of oestrogen in overweight postmenopausal women appeared to potentiate this effect. The second study in a large population-based cohort found that obese women had higher risk of GORD symptoms compared to obese men and the risk was highest among premenopausal women and postmenopausal women on oestrogen therapy. However, several other studies have found that the increased risk of acid-related oesophageal disease among overweight and obese persons was neither confounded nor modified by gender. The oestrogen hypothesis does not explain the gender- or race-related differences in GORD.

CLINICAL IMPLICATIONS

The commonly reported anecdote of new onset of GORD or exacerbation of existing symptoms with weight gain has been shown in a study by Nilsson et al who found that that a gain greater than 3.5 BMI units was associated with an approximately 3-fold increase in the risk of developing new reflux symptoms.41 A few studies found that weight loss improves GORD symptoms as well as oesophagitis in overweight persons,43 while other studies did not find such an effect.44 There are small non-randomised studies suggesting that weight loss following bariatric surgery for morbid obesity is associated with an improvement in GORD symptoms.45 There is no data on weight loss and the risk of oesophageal adenocarcinoma.

The accurate interpretation of the epidemiological data is that avoiding weight gain in the first place is associated with a lower risk of GORD.