This is one of the largest case-control studies to examine the association between dietary fat and meat intakes in humans and the risk of RE, BE, and EAC utilizing the same control group. Our data suggested that total fat, saturated fat, and monounsaturated fat intakes were adversely associated with the risk of RE and EAC. Plant-based fats (e.g. polyunsaturated fat) were not associated with RE or BE, but there was a suggestion of an adverse association with EAC risk. Cholesterol intake was also found to be a risk factor for EAC. Meat intakes were not associated with the majority of the case groups, although omitting processed meat from the total red meat intake variable (fresh red meat variable) resulted in a significantly positive association being reported for EAC. Processed meat intake was adversely associated with RE only.
The results presented in this current study with regards to BE are in agreement with those from a recent case-control study [14
]; both studies did not find consistent associations between fat intakes or cholesterol with BE risk, although [14
] did report non-significant inverse trends for polyunsaturated fat, which is not evident within this current study. However, two previous rat models have demonstrated adverse effects of total dietary fat or animal-fat on BE [26
]. Chen et al
. hypothesized that a high dietary animal-fat intake plays a crucial role in the development of BE and EAC, by inducing a significant increase in taurine-conjugated bile acids in bile juice, and by increasing the pH in the esophagus [27
]. Physiological studies of human volunteers have also shown increased frequency of transient lower esophageal sphincter relaxation and increased esophageal acid exposure with high fat consumption [28
]. Our results would seem to support these hypotheses because we found total fat, saturated fat, and monounsaturated fat to be strongly associated with increased RE and EAC risk, and the associations observed in this current study for EAC and fat have also been shown in other case-control studies [8
]. Therefore, our results suggest that higher animal (meat) based fat intakes may lead to increased exposure of the distal esophagus to excess acid, which may result in a metaplastic change of the epithelium leading to BE formation. Dietary fat intakes were not associated with BE risk, but the fact we found a strong association with EAC risk does suggestthat animal (meat) based fat intakes may be a risk factor for progression to cancer (not necessarily via BE). In addition, this finding supports the hypothesis that high fat intake may be at least partially responsible for the rising rates of EAC in the United States and Western Europe, as the fat content has increased in these diets. Our additional exploratory analysis of the individual meat and fish items with risk of RE, BE and EAC further supported this hypothesis e.g. patients in the fourth quartile of corned beef/luncheon meat (processed meat and a high source of saturated and monounsaturated fat) had a higher risk of RE and EAC.
Conversely, plant based foods are a key dietary source of polyunsaturated fats, and epidemiologic evidence suggests that a diet rich in plant based, high-fiber, low-fat foods, can provide protection against BE [14
] and EAC [20
]. However, polyunsaturated fat intake was not associated with RE or BE in this current study, but there was a suggestion of an adverse association with EAC risk; no consistent effect of intake on risk was observed. The finding that cholesterol intake was associated with EAC risk is also in agreement with other case-control studies [8
It was thought that the associations which we report for dietary fat intakes may not be attributable specifically to the various fats per se, but rather may reflect dietary patterns. This was because the adverse associations reported for the case groups tended to be from animal (meat) based fats (saturated fat and monounsaturated fat). However, it was not feasible to examine the association for animal fat and plant sources of fat separately within FINBAR because in order to do this we would have needed to know the contribution of foods to fat intake in the study and have detailed information on the type of fat used in cooking and at the table. Also it is impossible to know what fats were used in manufactured foods such as cakes/biscuits/pastries, and it is likely that it is a mixture of both animal and plant sources. Additionally, fat used in cooking or at the table was not defined well enough from the FFQ to categorize participants accurately in terms of animal versus plant sources. Fats used in take-away restaurants are also likely to vary hugely so we could not make an assumption that they used lard (animal) or sunflower oil (plant) to cook foods for example. Additionally, the total fish intake variable used in this study contained fried fish, and we do not have information on the type of fat used in frying, which could help explain the lack of associations reported. However, omitting fried fish from the total fish intake variable did not attenuate the results reported (data not shown).
Previous studies have reported an increased risk of EAC in relation to intakes of total meat [15
] and red meat [15
], whereas others reported no association between EAC and processed meat [17
] or red meat [19
], with a recent study also reporting a reduced risk of long-segment BE with higher meat intakes [14
]. A diet characterized by high intakes of red meat and processed meat was also shown to be associated with an increased risk of EAC [31
]. Even though the exact mechanisms remain unclear, several hypotheses have been suggested to explain possible causal relationships between meat intakes and cancer risk, including mutagens formed in meats cooked at high temperatures (heterocyclic amines and polycyclic aromatic hydrocarbons) and the endogenous formation of N-nitroso compounds, which are carcinogens found in abundance in processed meats [32
]. Unfortunately, we did not have information on cooking methods or doneness, and therefore could not investigate this hypothesis further within FINBAR. However, when we omitted processed meat from the total red meat variable (fresh red meat), it resulted in a significantly positive association being seen between fresh red meat intake and EAC risk. Therefore, it would appear that only fresh red meat has an adverse association with EAC risk, and not processed meat; processed meat intake was not associated with EAC either. However, processed meat intake was adversely associated with RE risk. Additionally, red meat and liver is a key dietary source of heme iron, which is more readily absorbed than iron from other sources, and is thought to contribute to carcinogenesis by generating free radicals and inducing oxidative stress [36
]. This heme iron hypothesis has been demonstrated in animal models [37
], but human data remains inconsistent [19
]. Additionally, heme iron from both red and processed meat has been shown to significantly increase the formation of N-nitroso compounds in the upper gastrointestinal tract, which may result in increased risk from esophageal cancer [44
]. The fact we also found significant adverse associations between EAC risk and liver intake in exploratory analyses further strengthens this heme iron hypothesis, and adds weight to the argument that increased risk of esophageal cancer may be promoted through the increased formation of N-nitroso compounds by heme iron. Cross et al. [35
] used liver pate and blood pudding as a heme-iron supplement and found increased fecal N-nitroso compounds compared with a low meat diet.
GER symptoms, smoking and alcohol consumption have been implicated in the RE-BE-EAC spectrum previously [45
]. Therefore, we evaluated interaction by doing stratified analysis and by evaluating interaction terms. However, the analysis of risk estimates and effect modification was limited by small case numbers within some of the stratum, and there was no evidence of interaction between dietary intakes with smoking, GER symptoms or alcohol intake for RE, BE or EAC patients.
There are several strengths to this study. The FINBAR study has a relatively large sample size, is population-based and used stringent inclusion criteria throughout. Information was collected on a wide range of potential confounders such as BMI, smoking status, H.pylori
, and GER symptoms. There are also limitations to this study including the possibility of residual confounding from unmeasured variables and the potential for recall bias. This is because the FFQ used recorded dietary intakes during a 12 month period, 5-years ago, and there would be a tendency for RE, BE or EAC patients to recall past intakes differently than healthy controls(selective recall). Also, within FINBAR, EAC patients were incident cases and were interviewed shortly after diagnosis. However, we did not have reliable information to confirm incident/prevalent BE cases as the diagnosis date was retrieved from patient histology reports, and therefore many may have been prevalent cases. When asked, many of the BE patients could not remember or did not know that they had a diagnosis. Therefore, patients were likely to have had BE long before diagnosis and this cannot be accurately determined. This inability of separating incident from prevalent BE is the same limitation seen for other asymptomatic pre-cursor lesions, such as colon polyps, and incident lesions can only be identified in cohorts with multiple endoscopic screenings. As for RE patients, there was no restriction placed on recruitment of incident or prevalent cases. Therefore, the fact that both incident/prevalent cases were recruited may also have resulted in recall bias of dietary intakes and stratification by incident/prevalent cases was not possible within FINBAR. Also, the response rate of the controls was lower compared with cases, which may have introduced selection bias. Nevertheless, the mean daily intake of total fat among controls (99.6 g/day) was similar to intake reported in the North/South Ireland Food Consumption Survey (approximately 90 g/day) [48
], suggesting that our controls are representative of the general population with regard to fat intake. Additionally, it is widely understood that the incidence of BE and EAC is higher among males than females, and this is reflected in the numbers recruited as part of FINBAR (). Population controls were frequency matched by sex and 5-year age band to the distribution of EAC patients to ensure that the age and sex profile of BE patients and population controls resembled that of the EAC cases.
Overall, the most recent review of the evidence by the World Cancer Research Fund & American Institute for Cancer Research, in 2007, concluded that no recommendation could be reliably made regarding intakes of total fat, saturated fat, monounsaturated fat or polyunsaturated fat and esophageal cancer risk, and there is currently limited suggestive evidence that higher intakes of red and processed meat can increase risk [49
]. Our data suggested that total fat, saturated fat, and monounsaturated fat intakes were adversely associated with the risk of RE and EAC. Meat intakes were not associated with RE, BE or EAC, although fresh red meat (excluding processed meat) was significantly associated with EAC risk, and processed meat was adversely associated with RE. Further studies, investigating the association between dietary fat intakes and food sources of fat are needed to confirm these results.
Previous epidemiological studies have examined the association between dietary fat and meat intakes, and esophageal cancer risk. However, results have been mixed and many studies did not differentiate between the specific cancers e.g. esophageal adenocarcinoma and esophageal squamous cell carcinoma. Additionally, associations between dietary fat and meat have not been widely researched. This study allowed us to look at total dietary fat and meat intakes, along with their subtypes concurrently in reflux esophagitis, Barrett’s esophagus and esophageal adenocarcinoma patients, and provided us with an opportunity to hypothesize at which stage in the carcinogenic pathway these intakes may have an effect.
The incidence of esophageal adenocarcinoma has dramatically increased in recent decades, and the outlook for patients diagnosed with esophageal adenocarcinoma remains poor. Therefore, successful prevention depends on the identification of modifiable risk factors, with diet being one such potential modifiable risk factor for both esophageal adenocarcinoma and its precursor state, Barrett’s esophagus. This study provides findings that could have significance for the growing number of people diagnosed with Barrett’s esophagus in order that they may minimize their risk of development of cancer.