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Keywords:

  • excess body weight;
  • gastrointestinal cancers;
  • liver cancer;
  • obesity;
  • overweight

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemic of obesity in the Asia-Pacific region
  5. Changes in prevalence of overweight and obesity in the Asia-Pacific region
  6. The problem of childhood obesity
  7. Relationship between obesity and GI-liver cancers
  8. Decrease body weight and cancer risk
  9. Conclusions
  10. References

Obesity is major health problem in the Asia-Pacific region. The proportion of people who are overweight and obese in the region has increased dramatically and is closely linked to the increasing affluence in the region. While the body mass index has been used as a yardstick in many published studies, it has been noted that Asian patients have a greater percentage body fat for a given body mass index and especially abdominal or visceral obesity.

The association of obesity and cancers is intriguing and worrisome at the same time, as obesity is rising exponentially throughout the world especially in the Asia-Pacific region. Evidence of its association with gastrointestinal cancers is well documented and is reported with cardioesophageal, colorectal, liver, pancreatic, and gallbladder cancers. The strength of association varies between individual cancers but is of particular concern with colorectal cancer, which is perhaps the fastest emerging cancer in this region. Biological mechanisms for obesity-related carcinogenesis have been described, which includes insulin resistance and secretion of adipokines and chronic inflammation. A “dose–response” relationship between severity of excess body weight and risks of cancer has been reported. However, there is a paucity of data looking at a decrease in incidence of these cancers with a decrease in body weight with treatment, for example, bariatric surgery. Such studies will be difficult to perform and which would require a long period of longitudinal follow-up.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemic of obesity in the Asia-Pacific region
  5. Changes in prevalence of overweight and obesity in the Asia-Pacific region
  6. The problem of childhood obesity
  7. Relationship between obesity and GI-liver cancers
  8. Decrease body weight and cancer risk
  9. Conclusions
  10. References

Obesity has reached epidemic proportions in the world today.[1, 2] The World Health Organization (WHO) has estimated that worldwide obesity has more than doubled from 1980 to 2008. It is thought that more than 1.4 billion adults, aged 20 years and older, are overweight and up to one quarter of them obese.[3] Overweight and obesity are leading risks for global deaths. It is estimated that at least 2.8 million adults die each year as a result of being overweight or obese.[3] The strong association of obesity with diabetes mellitus and ischemic heart disease is well known, but increasingly its association with cancers has also been recognized.[4]

Obesity therefore poses a huge health burden to the global population. We review the epidemiology of overweight and obesity in Asia and discuss the relationship between obesity and gastrointestinal (GI) and liver cancers with special reference to the Asia-Pacific region.

Epidemic of obesity in the Asia-Pacific region

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemic of obesity in the Asia-Pacific region
  5. Changes in prevalence of overweight and obesity in the Asia-Pacific region
  6. The problem of childhood obesity
  7. Relationship between obesity and GI-liver cancers
  8. Decrease body weight and cancer risk
  9. Conclusions
  10. References

The Asia-Pacific region has more than half the world's population of seven billion. It is also the region that has undergone the most marked socioeconomic and demographic changes in recent decades. Inevitably, such changes have been accompanied by urbanization and changes in lifestyle, leading to a change in dietary habits to more “high-calorie and nutrient-dense” foods, and a decrease in daily physical activity. This has resulted in an epidemic of obesity and overweight in this region.[5] Changes in health indices in the most populous region in the world will eventually have a pronounced effect on the global health status.

The prevalence of obesity and overweight in major Asian countries based on the WHO database are listed in Table 1. The rates for Australia (with a majority Western population) and the USA are included for comparison. Much of these data are derived from national health and nutritional surveys of individual countries.[6]

Table 1. Prevalence of overweight and obesity in Asia-Pacific countries[6]
CountryOverweight (%)Obese (%)
China18.92.9
India4.50.7
Japan23.23.1
Korea32.13.2
Malaysia26.55.8
Philippines24.04.3
Singapore26.25.7
Thailand28.77.0
Australia49.016.4
USA68.033.8

Based on WHO international body mass index (BMI), a broad comparison between Asian and Western populations can be made. If lower cut-off values are adopted for Asian patients as recommended, the reported prevalence rates for Asian countries would be higher.[7, 8] In general, however, the prevalence rates of obesity are still much lower compared with a Western population, although in several Asian countries such as Thailand, the proportion of overweight has reached almost similar levels.[5] BMI levels notwithstanding, it has been noted that Asians have a higher percentage of body fat and visceral adiposity for the same BMI compared with those of Western origin.[9-11] This has predisposed Asians to insulin resistance and development of type 2 diabetes mellitus and associated metabolic diseases.[5]

Changes in prevalence of overweight and obesity in the Asia-Pacific region

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemic of obesity in the Asia-Pacific region
  5. Changes in prevalence of overweight and obesity in the Asia-Pacific region
  6. The problem of childhood obesity
  7. Relationship between obesity and GI-liver cancers
  8. Decrease body weight and cancer risk
  9. Conclusions
  10. References

In a meta-analysis of nationally representative data from China, Wang et al. reported a rise of overweight and obesity in China, from 14.6% in 1992 to 21.8% in 2002 based on WHO international cut-off levels, and based on the Chinese obesity standard the increase was from 20.0% to 29.9%.[12] The annual increase rate was highest in males, urban residents, and high-income groups. Similar increases in obesity have been noted in other Asian countries. For example, the Malaysian National Health and Morbidity Survey (NHMS) showed that the prevalence of obese adults (BMI ≥ 30 kg/m2) rose from 5.8% in 1996 to 11.7% in 2006.[13] The third NHMS in Malaysia recently reported that the prevalence of overweight and obesity in men were 29.2% and 7.4%, respectively, whereas the prevalence in women were 30.3% and 13.8%, respectively.[13] Similarly in Singapore, the prevalence of obesity has increased from 5.5% in 1992 to 10.8% in 2010.[14]

The problem of childhood obesity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemic of obesity in the Asia-Pacific region
  5. Changes in prevalence of overweight and obesity in the Asia-Pacific region
  6. The problem of childhood obesity
  7. Relationship between obesity and GI-liver cancers
  8. Decrease body weight and cancer risk
  9. Conclusions
  10. References

Of greater concern are the increasing reports of childhood obesity in the Asian population. In a recent report, based on three national surveys, the prevalence of obesity was noted to increase by almost threefold among children in China.[15] An earlier study in China had also documented similar rise among school children in China.[16] Similar figures have been obtained from reports from Thailand and India.[17, 18] Childhood obesity portends further related problems in adulthood. A dilemma in Asia is the concomitant existence of overweight and obesity and undernutrition at the same time, which has been highlighted as a problem in developing countries of the world.[19]

Relationship between obesity and GI-liver cancers

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemic of obesity in the Asia-Pacific region
  5. Changes in prevalence of overweight and obesity in the Asia-Pacific region
  6. The problem of childhood obesity
  7. Relationship between obesity and GI-liver cancers
  8. Decrease body weight and cancer risk
  9. Conclusions
  10. References

Biological mechanisms

It is unclear how obesity exactly drives carcinogenesis and whether the putative biological mechanisms differ from cancer to cancer. It is almost certainly a multifactorial process. The most commonly discussed models of carcinogenesis are insulin resistance and the role of chronic inflammation. Both mechanisms are not mutually exclusive and may interact with each other.

Insulin-cancer hypothesis

Circulating insulin levels increased with obesity and many obese patients are insulin resistant. It is thought that hyperinsulinemia results in cancer through the growth-promoting effects of insulin.[20, 21] Chronic hyperinsulinemia results in a decrease in insulin growth factor binding protein 1 and 2 resulting in an increase in circulating insulin and more importantly insulin growth factor. This in turn results in decreased apoptosis and increased cell proliferation in the target tissues.[4] Studies have shown a correlation of an elevated C-peptide (a surrogate of circulating insulin) with breast cancer, colorectal, pancreatic, and endometrial cancer.[22]

Chronic inflammation and secretion of adipokines

Adipose tissue is a highly active “organ” resulting in secretion of various cytokines, chemokines, and hormones. Obesity results in a state of constant chronic inflammation whereby systemic pro-inflammatory markers such as C-reactive protein and interleukin-6 are elevated. Some of these cytokines can act directly in the promotion of cancer or else cancers could be the result of the chronic inflammatory process itself.

Adipokines are substances secreted by adipose tissue. Leptin and adiponectin are two adipokines that have been studied very thoroughly. Leptin is found to be increased in obesity. It is a pro-inflammatory hormone and has also been shown to be directly tumorigenic. It has been shown to be associated with colorectal cancer (CRC) in in vitro and animal studies. Serum leptin levels have been correlated with colorectal adenomas. Adiponectin, on the other hand, is inversely correlated with obesity and is known to have insulin-sensitizing function as well as anti-inflammatory activity. Adiponectin levels are found to be decreased in obese individuals. In epidemiological studies, higher serum adiponectin levels have been shown to be associated with a lower risk of prostate, colorectal, and endometrial cancers.[23]

Association with specific GI-liver cancers

The proportion of the cancer in a population that is attributable to a given risk factor or commonly called population attributable fraction (PAF) is calculated based on the relative risks (RRs) and the prevalence of the cancer in the population. The estimated PAF for several GI cancers in the US population is presented in Table 2 and gives us an overall impression of the association between obesity and specific cancers.[4]

Table 2. Obesity and gastrointestinal related cancers- relative risks (RR) and population attributable fraction (PAF) (adapted from Calle and Kaaks[4] with permission)
 RRPAF (%)
BMI 25–30 kg/m2BMI > 30 kg/m2
  1. BMI, body mass index.

Colorectal cancer (men)1.52.035.4
Colorectal cancer (women)1.21.520.8
Esophageal adenocarcinoma2.03.052.4
Gastric cardia adenocarcinoma1.52.035.5
Pancreatic cancer1.31.726.9
Gallbladder cancer1.52.025.5

Cardioesophageal cancer

The incidence of cardioesophageal adenocarcinoma has increased dramatically in the past two decades in the West. Over the same period of time, the prevalence of obesity has also increased correspondingly, and obesity has therefore been implicated as the causative factor.[24]

In a meta-analysis of 14 studies, Kubo and Corley[25] calculated an odds ratio (OR) of 1.7 (95% confidence interval [CI]: 1.6–1.9) for esophageal adenocarcinoma with a BMI >25.0. The OR was higher for males (2.2 [95% CI: 1.7–2.7]) compared with females (2.0 [95% CI: 1.4–2.9]). A lower OR was obtained for gastric cardia adenocarcinoma (1.2 [95% CI: 1.0–1.5]). The majority of studies were from the West. Studies from China were included but were few and not found to have a positive association. In general, cardioesophageal cancers in Asia, unlike in the West, have not been shown to have increased.

These cancers are thought to be mediated through the intermediate stage of development of Barrett's esophagus. However, the association between obesity and Barrett's esophagus has neither been shown to be strong nor consistent.[26]

Colorectal cancer

The greatest body of published literature on obesity and cancers has been with CRC and its precursor—colorectal adenomas.

In a large meta-analysis by Mogahddam and colleagues, the estimated RR of CRC comparing obese with normal body weight was 1.19 (95% CI: 1.11–1.29), men—1.41 (95% CI: 1.30–1.54), and women—1.08 (95% CI: 0.98–1.18) for women.[27] A dose–response relationship between BMI and CRC was found—the risk of CRC increased by 7% for a 2 kg/m2 increase in BMI.

In a recently published meta-analysis from Japan, Matsuo et al. reported a pooled analysis of eight population-based prospective cohort studies in Japan with > 300 000 subjects.[28] The adjusted hazard ratios (HRs) for 1 kg/m2 increase: male: 1.03 (95% CI: 1.02–1.04); females: 1.02 (95% CI: 1.00–1.03). There was no association with rectal cancers and a stronger association with proximal or right-sided colon cancers.

The association with colorectal adenomas is well summarized in study by Ben et al.[29] In an extensive meta-analysis of 36 studies with 30 000 cases of CRA, an RR of 1.19 (95% CI: 1.13–1.26) per five-unit increase in BMI was calculated, but this was not significant for rectal adenomas—RR 0.85 (95% CI: 0.74–0.99). Substratification of the subjects studied, into white and East Asian population showed an RR of 1.12 (95%CI: 1.04–1.21) for the former group and 1.29 (95% CI: 1.11–1.51) for Asian subjects.

In a Korean study, a positive association between abdominal obesity measured by waist circumference was shown (OR: 2.74 [95% CI: 1.66∼4.51] in men; OR: 2.58 [95% CI: 1.08∼6.12] in women).[30] Two Korean studies studied the association of visceral adiposity—utilizing computed tomography scan examination in all subjects—and colorectal adenomas. Oh et al. obtained an OR of 4.07 (95% CI: 1.01–16.43)[31] while Kang et al. obtained an OR of 3.09 (95% CI: 2.19–4.36) between the highest versus the lowest quintile.[32]

Liver cancer

Studies on the association with liver cancer have been from East Asia where the cancer is highly prevalent.

The Korean Cancer Prevention Study is a large 14-year prospective cohort study of 1 213 829 Koreans covered under the Korean National Health Insurance Corporation. In this study, Jee et al. calculated an HR of liver of 1.63 (95% CI: 1.27–2.10) for men and 1.39 (95% CI: 1.00–1.94) for women.[33]

Tanaka et al. analyzed the results of nine cohort studies: RR for one-unit increase in BMI (kg/m2) 1.07 (95% CI: 1.03–1.10]. Of three case–control studies, an RR of 1.31 (95% CI: 1.12–1.53) was calculated. Overweight/obese individuals were found to have an RR of 1.74 (95% CI: 1.33–2.28).[34] In a more extensive meta-analysis, Chen et al. on 26 prospective studies, 25 337 subjects calculated an RR of 1.48 (95% CI: 1.31–1.67) for subjects who were overweight or obese. For obese subjects, an RR of 1.83 (95% CI: 1.59–2.11) was obtained.[35] It is interesting to note that for subjects with liver disease and with hepatitis C infection but not those with hepatitis B infection, the effect of overweight and obesity was higher.

Pancreatic cancer

In the large PanScan study funded by the National Cancer Institute, USA, a positive association between increasing BMI and risk of pancreatic cancer was observed (adjusted OR for the highest vs lowest BMI quartile = 1.33, [95% CI = 1.12–1.58]. Among men, 1.33 [95% CI: 1.04–1.69] and women, 1.34 [95% CI: 1.05–1.70]).[36]

In a recent meta-analysis, Aune et al. analyzed 23 prospective studies of BMI and pancreatic cancer risk with 9504 cases included. The RR for pancreatic cancer for a five-unit increment was 1.10 (95% CI: 1.07–1.14, I2 = 19%). The RR for a 10-cm increase in waist circumference was 1.11 (95% CI: 1.05–1.18) and for a 0.1-unit increment in waist-to-hip ratio was 1.19 (95% CI: 1.09–1.31).[37]

Gallbladder cancer

Obesity has been linked to both gall stones and gallbladder cancer. Engeland et al. in a large population-based study found no association with an increased BMI for gallbladder cancer in men but a marked increase in women. The RR associated with a one-unit increase in BMI was 1.06 (95% CI: 1.04–1.07). The risk for women having BMI 35.0–39.9 and 40.0 compared with those having BMI 18.5–24.9 were 2.56 (95% CI: 1.96–3.35) and 2.77 (95% CI: 1.65–4.65), respectively.[38]

In a population-based study from Shanghai, Hsing et al. found that a BMI (≥ 25.0) was associated with an OR of 1.6 (95% CI: 1.2–2.1). Increasing waist–hip ratio was associated with an excess risk of gallbladder cancer risk, with those having a high BMI (≥ 25) and a high waist–hip ratio (> 0.90) having the highest risk of gall bladder cancer with an OR of 12.6 (95% CI: 4.8–33.2) compared with those with a low BMI and waist–hip ratio.[39]

Decrease body weight and cancer risk

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemic of obesity in the Asia-Pacific region
  5. Changes in prevalence of overweight and obesity in the Asia-Pacific region
  6. The problem of childhood obesity
  7. Relationship between obesity and GI-liver cancers
  8. Decrease body weight and cancer risk
  9. Conclusions
  10. References

Although the calculated risks with obesity vary between individual cancers, the association with GI cancers has been consistently reported in published studies. Furthermore a “dose–response” relationship has been demonstrated with an increased risk shown with progressively higher BMIs.

A critical set of evidence linking obesity causally with cancers is the demonstration of a decrease in cancer incidence with a sustained decrease in body weight. In the prospective 7-year follow-up Iowa Women's health study, post-menopausal women who experienced intentional weight loss ≥ 20 pounds had incidence rates lower by 11% for any cancer (RR = 0.89, 95% CI: 0.79–1.00) and by a non-significant 9% for colon cancer (RR = 0.91, 95% CI: 0.66–1.24).[40] In a large Austrian study with a follow-up period of also 7 years, Rapp et al. showed that the risk of colon cancer in men but not in women was halved (HR 0.50; 95% CI: 0.29–0.87] with weight loss.[41]

In a retrospective cohort study in Japan, the incidence of colorectal polyps following resection assessed at 1 year according to BMI and rates of colorectal adenoma were 9.3% in the weight-reduction group, 16.2% in the weight-gain group, and 17.1% in the no weight change group. The incidence of colorectal adenoma in the weight-reduction group was significantly lower than that in the non-reduction group (P = 0.01).[42]

Studies seeking to answer this question are inherently difficult to perform. Firstly, the prolonged duration of the Carcinogenic process requires a long follow-up period and secondly, the difficulty in achieving significant, consistent, and durable weight loss, which is probably best achieved only with bariatric surgery. In the well-conducted Swedish obesity subjects study in Sweden, a decrease in cancer incidence was seen in obese women (HR 0.58 [95%CI: 0.44–0.77]); but not in men (HR 0.97 [95% CI: 0.62–1.52]), up to an 18-year follow-up period.[43] In another study from Utah, USA, the overall cancer incidence was significantly lower in the gastric bypass group compared with controls (HR 0.76 [95% CI: 0.65–0.89]).[44] However, the most recent study with bariatric surgery did not show a decrease in cancer incidence with bariatric surgery and in fact reported an increase in CRC incidence.[45]

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemic of obesity in the Asia-Pacific region
  5. Changes in prevalence of overweight and obesity in the Asia-Pacific region
  6. The problem of childhood obesity
  7. Relationship between obesity and GI-liver cancers
  8. Decrease body weight and cancer risk
  9. Conclusions
  10. References

Although the causal link between obesity and cancers is not incontrovertible, there is sufficient evidence to indicate that it plays a significant role in the pathogenesis of several GI cancers especially CRC. CRC is the fastest emerging cancer in the Asia-Pacific region.[46] While efforts at implementing CRC screening strategies have been organized, obesity is a “preventable cause” of the cancer. Measures to improve the problem of obesity across Asia would be necessary not just to prevent cancers, but also the whole range of metabolic and cardiovascular disorders that are afflicting a whole population of Asian patients.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemic of obesity in the Asia-Pacific region
  5. Changes in prevalence of overweight and obesity in the Asia-Pacific region
  6. The problem of childhood obesity
  7. Relationship between obesity and GI-liver cancers
  8. Decrease body weight and cancer risk
  9. Conclusions
  10. References