Antioxidants and other vitamins/minerals

Dietary antioxidants such as vitamin C, vitamin E, Se and carotenoids are believed to have the potential to reduce tissue and/or DNA damage by scavenging reactive oxygen species and enhancing apoptosis⁽Reference Clarkson and Thompson²²⁾. Thus, a lack of these nutrients may increase cancer risk through oxidative stress, DNA damage and cell proliferation⁽Reference Klaunig and Kamendulis²³⁾. Previous studies have shown that markers of oxidative stress are increased in the presence of oesophagitis and its complications, both in humans⁽Reference Wetscher, Hinder and Bagchi²⁴⁾ and in animal models⁽Reference Wetscher, Hinder and Bagchi²⁵⁾. In addition, dietary antioxidants may help to modify the damaging effects of refluxed acid and bile in patients with GERD, thereby reducing the risk of developing Barrett's oesophagus and its progression to oesophageal adenocarcinoma. Animal studies have demonstrated that vitamin E or α-tocopherol inhibits the development of oesophageal adenocarcinoma through its antioxidant properties, and inadequate Se in the diet may promote carcinogenesis by enhancing oxidative stress⁽Reference Chen, Ding and Yang^26, Reference Hao, Zhang and Liu²⁷⁾. Below are summaries of epidemiological evidence of the relationship between various dietary antioxidants and the risks of oesophageal adenocarcinoma and Barrett's oesophagus.

Fruits and vegetables

Fruits and vegetables are sources of antioxidants, phytosterols, folic acid, and other substances which may inhibit carcinogenesis by various mechanisms including quenching free radicals and blocking the formation of N-nitroso compounds^(48–Reference Mirvish, Wallcave and Eagen⁵⁰⁾. Eleven studies have examined the association between fruits and vegetables and the risk of oesophageal adenocarcinoma, and the majority of the case–control studies have reported significant inverse associations⁽Reference Tzonou, Lipworth and Garidou^31, Reference Brown, Swanson and Gridley^35, Reference Cheng, Sharp and McKinney^42, Reference Navarro Silvera, Mayne and Risch^51–Reference Terry, Terry and Wolk⁵⁵⁾. In fact, one US study estimated that the population attributable risk, defined as the proportion of disease in the population attributable to a given risk factor, associated with low fruit and vegetable consumption was 15·3 (95 % CI 5·8, 34·6) %⁽Reference Engel, Chow and Vaughan⁵³⁾. Similarly, a Swedish study estimated that about 20 % of oesophageal adenocarcinoma was attributed to low consumption (less than three servings per d) of fruits and vegetables⁽Reference Terry, Lagergren and Hansen⁵⁶⁾.

However, two large cohort studies reported no association between total intake of fruits and vegetables and the risk of oesophageal adenocarcinoma⁽Reference Freedman, Park and Subar^57, Reference Gonzalez, Pera and Agudo⁵⁸⁾. In the NIH-AARP Diet and Health study that included 5 years of follow-up (2 193 751 individual years) and 213 oesophageal adenocarcinoma cases, higher intake of fruits and vegetables was not associated with risk of oesophageal adenocarcinoma (HR 0·99; 95 % CI 0·61, 1·61; Q5 v. Q1)⁽Reference Freedman, Park and Subar⁵⁷⁾. Similarly, the European Prospective Study of Cancer and Nutrition (EPIC) with fewer cases (n 65) reported no associations with intake of fruits or vegetables (fruit: HR 0·94, 95 % CI 0·49, 1·80; vegetables: HR 0·71, 95 % CI 0·34, 1·48; 3rd v. 1st tertile (T))⁽Reference Gonzalez, Pera and Agudo⁵⁸⁾.

The beneficial effect of vegetables may be specific to certain botanical groups or types of vegetables. Dark green and cruciferous vegetables contain high levels of isothiocyanates and indole-3-carbinol which are thought to protect against the development of cancer⁽Reference Steinmetz and Potter⁵⁹⁾. Some epidemiological studies support this hypothesis. A recent study reported an inverse association between the intake of anthocyanidin, a flavonoid found commonly in raw vegetables, and the risk of oesophageal adenocarcinoma among white males⁽Reference Bobe, Peterson and Gridley⁶⁰⁾. In case–control studies that have evaluated the intake of specific types of vegetables, stronger inverse associations were reported between oesophageal adenocarcinoma and the intake of dark green, leafy green, or raw vegetables⁽Reference Brown, Swanson and Gridley^35, Reference Zhang, Kurtz and Yu^36, Reference Navarro Silvera, Mayne and Risch^51, Reference Chen, Ward and Graubard⁵⁴⁾. In addition, the NIH-AARP cohort study demonstrated that spinach intake was significantly associated with reduced oesophageal adenocarcinoma risk (HR 0·66; 95 % CI 0·46, 0·95) and a borderline significant inverse association was found for cruciferous vegetables such as cabbage and broccoli (HR 0·69; 95 % CI 0·48, 1·00)⁽Reference Freedman, Park and Subar⁵⁷⁾. Similarly, the EPIC cohort study reported a borderline significant inverse association between leafy vegetables (excluding cabbage) and the risk of oesophageal adenocarcinoma (OR 0·35, 95 % CI 0·12, 1·04; T3 v. T1)⁽Reference Gonzalez, Pera and Agudo⁵⁸⁾.

Three population-based case–control studies have evaluated the associations between the intake of fruits and vegetables and the risk of Barrett's oesophagus, and all have reported significant inverse associations⁽Reference Kubo, Levin and Block^37, Reference Anderson, Watson and Murphy^52, Reference Thompson, Beresford and Kirk⁶¹⁾. A study from Ireland reported a 40 % reduction in risk among those with more than thirty-four portions of fruits and vegetables per week, compared with those with less than twenty portions per week, though adjustment for GERD attenuated the association⁽Reference Anderson, Watson and Murphy⁵²⁾. Similarly, a study from Kaiser Permanente reported a significant inverse association when the fruit and vegetable intake of Barrett's oesophagus cases was compared with that of population controls. However, when cases were compared with GERD controls, the association was no longer significant⁽Reference Kubo, Levin and Block³⁷⁾, suggesting that among GERD patients, intake of fruits and vegetables did not modify the risk. No cohort studies evaluated the association between fruits and vegetables and the risk of Barrett's oesophagus.

Given the potential protective effect of fruit and vegetable intake, a randomised intervention trial was conducted to evaluate whether short-term dietary modification affects the progression of Barrett's oesophagus into cancer⁽Reference Kristal, Blount and Schenk⁶²⁾. In this trial, eighty-seven patients were randomised to an intensive, low-fat, high-fruit and vegetable diet plus weight loss group or to a control group, and biopsies were obtained at baseline, and at 18 and 36 months after the intervention. Ki67/DNA content flow cytometry was used to assess percentage Ki67-positive proliferating diploid G₁ cells, percentage total Ki67-positive proliferating cells, presence of aneuploidy, and presence of>6 % of cells in the 4N (G₂/tetraploid) fraction of the cell cycle, all of which are markers of cellular proliferation in Barrett's oesophagus⁽Reference Reid, Prevo and Galipeau^44, Reference Kristal, Blount and Schenk⁶²⁾. The intervention was effective at increasing fruit and vegetable consumption and promoting weight loss (P < 0·01), though no significant effect on any biomarker of cellular proliferation was observed. Another Seattle study reported no association between fruit and vegetable intake and DNA content flow cytometry in Barrett's oesophagus patients⁽Reference Moe, Kristal and Levine⁴¹⁾. Thus, short-term dietary modification does not appear to be effective in the progression to oesophageal adenocarcinoma among patients with Barrett's oesophagus. However, given the long latency period for disease progression, longer periods of intervention may be required.

Which components of fruits and vegetables are aetiologically relevant and at what points in the carcinogenesis process of oesophageal adenocarcinoma their intake may have an impact remain unclear. There are numerous known and unknown compounds in fruits and vegetables, and it is impossible to isolate their effects. One study evaluated whether other nutrients confound the observed strong inverse association between fruits and vegetables and Barrett's oesophagus: adjustment for obesity, total energy, intakes of folic acid, total fat, saturated fat, trans-fat, cholesterol, meat, isoflavones or fibre made no difference in the effect estimates, suggesting that a diet rich in fruits and vegetables is not simply a surrogate for other dietary factors⁽Reference Kubo, Levin and Block⁶³⁾. However, residual confounding remains a possibility in observational studies.

In addition, the presence of GERD symptoms may influence health-related behaviours among Barrett's oesophagus and oesophageal adenocarcinoma patients. The presence of GERD is one of the strongest risk factors for both Barrett's oesophagus and oesophageal adenocarcinoma⁽Reference Kamangar, Chow and Abnet¹⁶⁾, and GERD patients are commonly advised to reduce their consumption of citrus or other acidic fruits and vegetables⁽Reference DeVault and Castell⁶⁴⁾. Thus, reverse causation may bias observational studies, even prospective cohort studies, since patients often experience GERD for many years before their cancer diagnosis. Indeed, studies that have adjusted for GERD symptoms have reported partial attenuation in the inverse association⁽Reference Kubo, Levin and Block^37, Reference Anderson, Watson and Murphy⁵²⁾. However, this also suggests the possibility that at least some of the effect of fruit and vegetable intake on disease risk is independent of GERD.

In sum, the current evidence suggests that fruits and vegetables, particularly raw fruits and vegetables, dark green leafy vegetables, and cruciferous vegetables, may reduce the risk of Barrett's oesophagus and oesophageal adenocarcinoma. The current evidence also suggests that if there is a protective effect, it may take place early in the carcinogenesis process, given the strong inverse association between the intake of fruits and vegetables and Barrett's oesophagus, and the lack of association with the progression of Barrett's oesophagus into cancer. Evidence from cohort studies will help elucidate the relationships between the intake of fruits and vegetables and the risk of Barrett's oesophagus.

Carbohydrate

A recent ecological study reported a correlation between the rise in carbohydrate consumption in the USA and the increase in the incidence of oesophageal adenocarcinoma⁽Reference Thompson, Khiani and Chak⁶⁵⁾. Chronic insulin resistance, hyperglycaemia and hyperinsulinaemia have been implicated as potential risk factors for cancers of the breast, prostate, lung and colon. Since both high-carbohydrate and high-glycaemic index diets have been linked as possible contributors to these risk factors, carbohydrate intake has also been hypothesised to affect the risk of oesophageal adenocarcinoma⁽Reference Becker, Dossus and Kaaks^66–Reference Kaaks and Lukanova⁶⁹⁾. Insulin resistance and altered levels of insulin-like growth factor-related compounds also have been reported to influence the healing of oesophageal mucosal injury and oesophageal cell apoptosis⁽Reference Tchorzewski, Qureshi and Duncan^70–Reference Hollowood, Lai and Perks⁷⁴⁾. However, only limited epidemiological evidence is available on the relationships between carbohydrate intake and the risks of oesophageal adenocarcinoma and Barrett's oesophagus.

Six studies have examined the association between carbohydrate intake and the risk of oesophageal adenocarcinoma and one study evaluated the association with Barrett's oesophagus. Case–control studies have reported an inverse association between total carbohydrate intake and the risk of oesophageal adenocarcinoma⁽Reference Chen, Tucker and Graubard^28, Reference Mayne, Risch and Dubrow^29, Reference Mulholland, Cantwell and Anderson⁷⁵⁾, though not in all⁽Reference Tzonou, Lipworth and Garidou^31, Reference Brown, Swanson and Gridley^35, Reference Zhang, Kurtz and Yu³⁶⁾. The Factors Influencing the Barrett's Adenocarcinoma Relationship (FINBAR) study conducted in Ireland included cases with reflux oesophagitis, oesophageal adenocarcinoma and long-segment Barrett's oesophagus, and reported that intakes of total carbohydrate, starch and total sugar were associated with significantly lower risks of oesophageal adenocarcinoma, but not with Barrett's oesophagus⁽Reference Mulholland, Cantwell and Anderson⁷⁵⁾. On the other hand, glycaemic index was positively associated with the risk of oesophageal adenocarcinoma (OR 1·41; 95 % CI 1·05, 1·89; per 10 units/d increment). In addition, total carbohydrate intake and total sugar intake were inversely associated with the risk of reflux oesophagitis, a risk factor for Barrett's oesophagus (OR 0·67; 95 % CI 0·42, 1·04; per 50 g/d increment in total carbohydrate; OR 0·54; 95 % CI 0·35, 0·82; per 50 g/d increment in total sugar, respectively), though total carbohydrate was of borderline significance. On the other hand, starch intake was positively associated with risk of reflux oesophagitis (OR 2·25; 95 % CI 1·15, 4·41; per 50 g/d increment in starch).

How carbohydrate intake might affect the aetiology of oesophageal adenocarcinoma remains unclear. It is possible that a high carbohydrate intake is a proxy for a higher intake of whole grains or fruits and vegetables that are rich in other bioactive micronutrients⁽Reference Chen, Tucker and Graubard^28, Reference Mulholland, Cantwell and Anderson⁷⁵⁾, a lower intake of fat or animal products, or other suggested risk factors for oesophageal adenocarcinoma discussed below.

Fibre

Nine studies have examined the association between fibre and oesophageal adenocarcinoma. Most case–control studies of oesophageal adenocarcinoma have reported strong, significant inverse associations between fibre intake and disease risk⁽Reference Chen, Tucker and Graubard^28, Reference Mayne, Risch and Dubrow^29, Reference Tzonou, Lipworth and Garidou^31, Reference Brown, Swanson and Gridley^35, Reference Mulholland, Cantwell and Anderson^75, Reference Wu, Tseng and Hankin⁷⁶⁾. Earlier, smaller case–control studies also reported inverse associations between fibre and oesophageal adenocarcinoma, although some combined both gastric cardia and oesophageal adenocarcinoma into one outcome⁽Reference Tzonou, Lipworth and Garidou^31, Reference Zhang, Kurtz and Yu³⁶⁾. However, one of these studies reported a significant adverse association between total fibre and oesophageal adenocarcinoma⁽Reference Kabat, Ng and Wynder³⁴⁾, and a Swedish study also reported a borderline adverse association for intake of fibre from fruits and oesophageal adenocarcinoma⁽Reference Terry, Lagergren and Ye⁷⁷⁾.

Only two studies have evaluated the association between fibre intake and the risk of Barrett's oesophagus. In the FINBAR study, the risk of Barrett's oesophagus was significantly reduced in those in the highest v. the lowest tertile of fibre intake (OR 0·44; 95 % CI 0·25, 0·80), and the inverse association persisted even after controlling for fat, protein, starch and sugar intake⁽Reference Mulholland, Cantwell and Anderson⁷⁵⁾. Similarly, a Kaiser Permanente study reported that total fibre intake was inversely related to Barrett's oesophagus, though when stratified by fibre source, only fibre from fruits and vegetables (but not grains or beans) was associated with lower disease risk, raising the possibility that other food elements in fruits and vegetables may confound the association⁽Reference Kubo, Block and Quesenberry⁷⁸⁾.

There are a few potential mechanisms through which fibre intake might affect the aetiology of Barrett's oesophagus or oesophageal adenocarcinoma. A recent study demonstrated that inositol hexaphosphate, a naturally occurring polyphosphorylated carbohydrate found in food sources high in fibre, inhibited the cell growth rate of Barrett's-associated oesophageal adenocarcinoma cells in vitro by reducing cellular proliferation and promoting apoptosis⁽Reference McFadden, Riggs and Jackson⁷⁹⁾. In addition, a diet rich in fibre is associated with lower plasma levels of biomarkers of systemic inflammation such as TNF-α receptor-2 and IL-6, potentially affecting the carcinogenesis process⁽Reference Ma, Hebert and Li⁸⁰⁾. Also, fibre itself may absorb carcinogens from food items that pass through the digestive tract⁽Reference Brown, Swanson and Gridley³⁵⁾, or reduce the risk of Barrett's oesophagus by decreasing the risk of hiatus hernia⁽Reference Burkitt⁸¹⁾. However, similar to carbohydrate intake, the possibility that a high-fibre diet is a proxy for a diet rich in fruits and vegetables or micronutrients that are protective against these diseases cannot be ruled out. In sum, although the mechanisms remain unclear, current evidence suggests a strong inverse association between dietary fibre and the risk of oesophageal adenocarcinoma. More studies are needed to evaluate the relationship between fibre intake and the risk of Barrett's oesophagus, and results from cohort studies will help shed light on the association with oesophageal adenocarcinoma.

Folate (folic acid)

Another nutrient of interest in fruits and vegetables, particularly green leafy vegetables, is folate. Previous studies have linked folate intake and genetic polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), a central enzyme in folate metabolism, with colorectal cancer⁽Reference Sanjoaquin, Allen and Couto^82, Reference Kono and Chen⁸³⁾. Certain folate-metabolising enzyme genotypes are associated with an increased risk of gastric cardia adenocarcinoma and oesophageal squamous cell carcinoma⁽Reference Larsson, Giovannucci and Wolk^84, Reference Stolzenberg-Solomon, Qiao and Abnet⁸⁵⁾. Also, folate deficiency has been hypothesised to increase the risk of cancer via mediation by p53 tumour suppressor gene⁽Reference Balbuena and Casson⁸⁶⁾, or by decreasing intracellular S-adenosylmethionine which inhibits cytosine methylation in DNA, activating proto-oncogenes, inducing malignant transformations, causing DNA precursor imbalances, misincorporating uracil into DNA, and promoting chromosome breakage⁽Reference Duthie⁸⁷⁾. A recent small study evaluating the effect of dietary folate and vitamin B₆ on p53 mutations in oesophageal adenocarcinoma reported that dietary intake was not associated with p53 mutations, p53 mutations at CpG sites and p53 protein overexpression⁽Reference Balbuena and Casson⁸⁶⁾.

Four studies have examined the association between folate and the risk of oesophageal adenocarcinoma; all reported inverse associations, though some were of borderline significance⁽Reference Chen, Tucker and Graubard^28, Reference Mayne, Risch and Dubrow^29, Reference Brown, Swanson and Gridley^35, Reference Zhang, Kurtz and Yu³⁶⁾. A recent meta-analysis including these studies reported that individuals in the highest folate intake category were at half the risk of developing oesophageal adenocarcinoma compared with those in the lowest category (summary OR 0·50; 95 % CI 0·39, 0·65)⁽Reference Larsson, Giovannucci and Wolk⁸⁴⁾. No studies have evaluated the association between folate and Barrett's oesophagus, progression from Barrett's oesophagus into cancer, or the role of functional polymorphisms in genes encoding folate-metabolising enzymes on the risk of oesophageal adenocarcinoma or Barrett's oesophagus.

It is important to note that alcohol (a folate antagonist), smoking (which impairs folate status), and other methyl-related nutrients (for example, vitamin B₆, vitamin B₁₂ and methionine) have an impact on the folate metabolic pathway, and may interact with folate and MTHFR polymorphisms to affect cancer risk⁽Reference Bailey⁸⁸⁾. In the studies of gastric cardia adenocarcinoma, strong effect modification has been observed between the MTHFR C677T polymorphism and alcohol drinking⁽Reference Larsson, Giovannucci and Wolk⁸⁴⁾. However, no studies to date have evaluated the interaction of dietary factors (i.e. alcohol and methyl-related nutrients) and folate-related genetic polymorphisms in relation to oesophageal adenocarcinoma. In summary, there is evidence that dietary folate may reduce the risk of oesophageal adenocarcinoma. Studies are needed to evaluate its effect on Barrett's oesophagus, progression from Barrett's oesophagus into cancer, and its interaction with potential effect modifiers including genetic polymorphism and alcohol consumption.

Meat, heterocyclic amines and nitrate/nitrite

Meat intake has been linked to several cancers, including colorectal, breast and prostate cancers⁽Reference Zheng and Lee^89, Reference Norat, Lukanova and Ferrari⁹⁰⁾. Eight studies have examined the association between meat intake and the risk of oesophageal adenocarcinoma, and one has studied the association with Barrett's oesophagus. The results are mixed. In the EPIC prospective cohort study that involved a mean follow-up of 6·5 years and sixty-five newly diagnosed cases of oesophageal adenocarcinoma, a positive association was observed for processed meat (HR 3·54; 95 % CI 1·57, 7·99; T3 v. T1) while the result for total meat intake was not significant (HR 1·79; 95 % CI 0·86, 3·75; T3 v. T1)⁽Reference Gonzalez, Jakszyn and Pera⁹¹⁾. In a multicentre, population-based case–control study, total meat intake was associated with an increased risk of oesophageal adenocarcinoma (OR 1·43; 95 % CI 1·11, 1·83; per serving/d), with red meat most strongly related to disease risk (OR 2·49; 95 % CI 1·39, 4·46; per serving/d)⁽Reference Navarro Silvera, Mayne and Risch⁵¹⁾. In the same study population, animal protein intake was associated with an increased risk of oesophageal adenocarcinoma, while vegetable protein intake was inversely related to risk⁽Reference Mayne, Risch and Dubrow²⁹⁾. However, a few case–control studies have reported no link between total or red meat intake and the risk of oesophageal adenocarcinoma⁽Reference Brown, Swanson and Gridley^35, Reference Zhang, Kurtz and Yu^36, Reference Chen, Ward and Graubard⁵⁴⁾. Also, a recent study of Barrett's oesophagus reported that total meat intake was inversely related to long-segment Barrett's oesophagus (OR 0·25; 95 % CI 0·09, 0·72)⁽Reference Kubo, Block and Quesenberry⁷⁸⁾, although this study did not stratify the results by type of meat. With regard to poultry intake, some studies have reported significant inverse associations with oesophageal adenocarcinoma⁽Reference Navarro Silvera, Mayne and Risch^51, Reference Gonzalez, Jakszyn and Pera⁹¹⁾, while others have reported borderline significant or positive associations⁽Reference Chen, Tucker and Graubard^28, Reference Zhang, Kurtz and Yu³⁶⁾.

The inconsistency in results may at least partially be due to a combination of factors such as the type of meat, nutrient content (for example, fat, protein, Fe), nitrite/nitrate content, and/or meat preparation methods (for example, cooking or preserving methods). Meats cooked at high temperatures (i.e. frying and grilling) and for a long duration contain heterocyclic amines and polycyclic aromatic hydrocarbons, potent mutagens that have been shown to induce tumours in animal models⁽Reference Zheng and Lee⁸⁹⁾. Total heterocyclic amine intake was positively associated with the risk of upper aerodigestive tract cancers in a study conducted in Uruguay⁽Reference De Stefani, Ronco and Mendilaharsu⁹²⁾. However, existing studies of oesophageal adenocarcinoma and Barrett's oesophagus have shown no association with cooking method/barbecued meat or well-cooked meat⁽Reference Kubo, Block and Quesenberry^78, Reference Terry, Lagergren and Wolk^93, Reference Ward, Sinha and Heineman⁹⁴⁾. In addition, processed meat is a major source of nitrites and nitrosamines and a recent systematic review of epidemiological studies suggested an association between processed meat and the risk of oesophageal cancers⁽Reference Jakszyn and Gonzalez⁹⁵⁾. N-nitroso compounds are strong animal carcinogens and have been shown to cause cancers of the nasal cavity, oesophagus and stomach in several animal models⁽Reference Lijinsky and Kovatch^96–Reference Preussmann, Habs and Habs⁹⁸⁾, and are considered ‘probably’ carcinogenic to humans⁽⁴⁸⁾. Although few studies have examined the relationship between intake of nitrite or nitrate and risk of oesophageal adenocarcinoma, the US multicentre study reported a borderline significant positive association for dietary nitrite intake (OR 1·17; 95 % CI 1·00, 1·36)⁽Reference Mayne, Risch and Dubrow²⁹⁾, and another study reported a non-significant positive association between dietary nitrite from animal sources and the risk of oesophageal adenocarcinoma⁽Reference Ward, Heineman and Markin⁹⁹⁾. In addition, this study found a significant interaction between vitamin C and nitrite intakes: those with low vitamin C and high nitrite intake were at significantly higher risk of developing oesophageal adenocarcinoma compared with those with high vitamin C and low nitrite intake (OR 2·72; 95 % CI 1·73, 4·27)⁽Reference Mayne, Risch and Dubrow²⁹⁾. In the same study population, however, meat with high nitrite was not associated with disease risk⁽Reference Navarro Silvera, Mayne and Risch⁵¹⁾. No study has evaluated the association between nitrite/nitrate and the risk of Barrett's oesophagus or progression. Since pesticides on fruits and vegetables are another major source of nitrate, the effects of nitrite/nitrate exposure on disease risk have significant public health implications and should be considered before encouraging high-risk individuals to indiscriminantly consume large amounts of fruits and vegetables.

In sum, evidence from cohort studies suggests an adverse association between meat intake and the risk of oesophageal adenocarcinoma, particularly for red meat and processed meat. Further research is needed to evaluate types of meat and the risk of Barrett's oesophagus, and the role of nitrite and nitrate, heterocyclic amines and polycyclic aromatic hydrocarbons in the aetiology of oesophageal adenocarcinoma and Barrett's oesophagus.

Fat

Given the established relationships between obesity and the risk of Barrett's oesophagus and oesophageal adenocarcinoma⁽Reference Kamangar, Chow and Abnet¹⁶⁾, a diet rich in fat is a suspected risk factor for these outcomes. Animal studies have reported an adverse effect of fat intake (total or animal) on Barrett's oesophagus⁽Reference Clark, Smyrk and Mirvish^100, Reference Chen, Mukaisho and Sugihara¹⁰¹⁾. Among the seven case–control studies that evaluated the association between fat intake and the risk of oesophageal adenocarcinoma, four reported an increased risk among individuals with high total fat intake compared with those in the lowest category of fat intake⁽Reference Chen, Tucker and Graubard^28, Reference Mayne, Risch and Dubrow^29, Reference Kabat, Ng and Wynder^34, Reference Zhang, Kurtz and Yu³⁶⁾, but three reported no association⁽Reference Tzonou, Lipworth and Garidou^31, Reference Brown, Swanson and Gridley^35, Reference Terry, Lagergren and Wolk¹⁰²⁾. The only case–control study that evaluated the effect of fat on the risk of Barrett's oesophagus found no association for total fat⁽Reference Kubo, Block and Quesenberry⁷⁸⁾. Lastly, modification of the diet by lowering fat and increasing fruit and vegetable consumption had no effect on the progression of Barrett's oesophagus as measured by DNA content flow cytometry⁽Reference Kristal, Blount and Schenk⁶²⁾.

The discrepancy in findings between studies may come from a lack of specification of fat or fatty acid types. For instance, trans-fats and saturated fats have been found to influence systemic inflammation such as TNF-α receptors 1 and 2⁽Reference Mozaffarian, Pischon and Hankinson¹⁰³⁾. A previous study reported that the epithelial expression of TNF-α increases with progression along the metaplasia–dysplasia–carcinoma sequence, suggesting an important role of TNF-α in the carcinogenesis process from Barrett's oesophagus into oesophageal adenocarcinoma⁽Reference Tselepis, Perry and Dawson¹⁰⁴⁾.

On the other hand, PUFA and n-3 fatty acids, mainly found in plants and fish, may decrease the risk of oesophageal adenocarcinoma. n-3 Fatty acids have been found to reduce cyclo-oxygenase 2 (COX-2) protein concentrations in Barrett's tissues in a small randomised study⁽Reference Mehta, Boddy and Cook¹⁰⁵⁾. Up-regulation of COX-2 has been shown to occur in both Barrett's oesophagus and oesophageal adenocarcinoma⁽Reference Wilson, Fu and Ramanujam¹⁰⁶⁾. Also, in vitro studies have demonstrated that COX-2 can reduce the rate of apoptosis⁽Reference Liu, Yao and Kirschenbaum¹⁰⁷⁾. Corroborating the findings of these laboratory studies, a few epidemiological studies of oesophageal adenocarcinoma and Barrett's oesophagus have reported an inverse association between disease risk and either fish intake or a dietary pattern rich in fish⁽Reference Chen, Tucker and Graubard^28, Reference Zhang, Kurtz and Yu^36, Reference Kubo, Levin and Block^108, Reference Bahmanyar and Ye¹⁰⁹⁾. These findings underscore the importance of differentiating the types or sources of fats and fatty acids when studying diet–disease relationships. Differentiation may help in making more targeted dietary recommendations, rather than, for example, suggesting a reduction in total fat intake, which risks limiting the intake of potentially beneficial types of fats or fatty acids.

Only a few epidemiological studies to date have evaluated different types of fatty acids. One study found an adverse association between saturated fat or cholesterol intake and the risk of oesophageal adenocarcinoma⁽Reference Mayne, Risch and Dubrow²⁹⁾, and a study of Barrett's oesophagus reported an adverse association with trans-fat and saturated fat intake when examined continuously (data not shown), while n-3 fatty acids were inversely related to the risk of Barrett's oesophagus⁽Reference Kubo, Block and Quesenberry⁷⁸⁾. However, the overall data are inconclusive, as other studies have found no association with saturated fat or cholesterol intake⁽Reference Tzonou, Lipworth and Garidou^31, Reference Brown, Swanson and Gridley³⁵⁾, and no other studies have evaluated the effects of n-3 fatty acids or trans-fat intake. More studies, especially cohort studies, are needed to better understand the relationships between various types of fat and the risks of oesophageal adenocarcinoma and Barrett's oesophagus.

Carbonated soft drinks

Carbonated soft drinks have been suggested as a risk factor for oesophageal adenocarcinoma because they are acidic and may increase reflux by reducing oesophageal sphincter pressure⁽Reference Hamoui, Lord and Hagen¹¹⁰⁾, though there has been little scientific evidence to support an association. Among the three studies that evaluated the association between carbonated soft drink consumption and the risk of oesophageal adenocarcinoma, two large case–control studies in Sweden and Australia have reported no relationship⁽Reference Lagergren, Viklund and Jansson^111, Reference Ibiebele, Hughes and O'Rourke¹¹²⁾. In contrast, a US multicentre study reported a strong inverse relationship between carbonated soft drink intake and oesophageal adenocarcinoma (OR 0·47; 95 % CI 0·29, 0·76)⁽Reference Mayne, Risch and Dubrow¹¹³⁾. Therefore, the current data show no conclusive evidence that soft drink consumption increases the risk of oesophageal adenocarcinoma, and no studies have evaluated its relationship with Barrett's oesophagus or progression of Barrett's oesophagus into cancer.

Iron

In animal models, Fe supplementation before reflux-induced oesophageal injury substantially increased the risk of oesophageal metaplasia and oesophageal adenocarcinoma, and the cells in these models demonstrated oxidative damage⁽Reference Chen, Ding and Yang^26, Reference Chen, Yang and Ding¹¹⁴⁾. In addition, the effect of Fe on oesophageal adenocarcinoma aetiology has been hypothesised because males are at higher risk for oesophageal adenocarcinoma and Barrett's oesophagus, and they typically have higher Fe saturation levels compared with females⁽Reference Barton, Acton and Dawkins^115–Reference Beutler and West¹¹⁷⁾.

However, the epidemiological evidence related to Fe and the risk of oesophageal adenocarcinoma or Barrett's oesophagus is not consistent with the hypothesis that Fe overload is a risk factor. In fact, three of the population-based case–control studies that evaluated this association suggested inverse associations⁽Reference Mayne, Risch and Dubrow^29, Reference Brown, Swanson and Gridley^35–Reference Zhang, Kurtz and Yu³⁶⁾, and the only study of Barrett's oesophagus also reported that levels of dietary Fe and serum Fe stores (ferritin and transferrin saturation) were lower among cases⁽Reference Corley, Kubo and Levin¹¹⁸⁾. In sum, there is currently no evidence that dietary Fe intake or Fe stores are adversely associated with the risk of oesophageal adenocarcinoma or Barrett's oesophagus. On the contrary, the evidence suggests inverse association with these outcomes.

Dietary patterns

Dietary factors are often strongly correlated and it is difficult to isolate the effect of a single factor. Individuals who differ in the consumption of one dietary component tend to differ in intake of other components. For instance, an individual with a high fibre intake may also have a high intake of fruits, vegetables and carbohydrates, and consume a diet lower in meat and fat. This issue of correlated variables in diet-related epidemiological studies makes it difficult to pinpoint the dietary component most likely to influence disease aetiology. Compared with the conventional analytical approach that focuses on individual dietary factors, studying dietary patterns more effectively captures the complexity of dietary habits. By identifying the most common dietary patterns in a population, researchers can evaluate the overall effects of nutrients and food items consumed in combination. In addition, dietary pattern analysis is potentially useful in formulating dietary recommendations because it may be easier for patients to understand and incorporate recommendations for dietary patterns rather than increase or decrease their intake of a particular nutrient⁽¹¹⁹⁾.

Two studies have examined the association between dietary pattern and the risk of oesophageal adenocarcinoma and one has reported on the association with Barrett's oesophagus. A Swedish study reported that a ‘healthy’ dietary pattern characterised by a high intake of vegetables, fruits, fish and poultry was associated with a lower risk of oesophageal adenocarcinoma, and that a Western-style diet rich in processed meat, red meat, sweets and fast foods was associated with an increased risk of oesophageal adenocarcinoma, though the results were not statistically significant⁽Reference Bahmanyar and Ye¹⁰⁹⁾. Another study reported that a high-meat dietary pattern had a borderline significant positive relationship with oesophageal adenocarcinoma risk (OR 3·6; 95 % CI 0·96, 13·2)⁽Reference Chen, Ward and Graubard⁵⁴⁾. A case–control study of Barrett's oesophagus also reported a significant inverse association between disease risk and a dietary pattern rich in fruits, vegetables and non-fried fish, along with a suggestive adverse association for a Western-style dietary pattern characterised by a higher intake of fast food and meat⁽Reference Kubo, Levin and Block¹⁰⁸⁾.