Objective Gastro-oesophageal reflux is a public health concern which could have associated oesophageal complications, including adenocarcinoma, and possibly also head-and-neck and lung cancers. The aim of this study was to test the hypothesis that reflux increases all-cause and cancer-specific mortalities in an unselected cohort.
Design The Nord-Trøndelag health study (HUNT), a Norwegian population-based cohort study, was used to identify individuals with and without reflux in 1995–1997 and 2006–2008, with follow-up until 2014. All-cause mortality and cancer-specific mortality were assessed from the Norwegian Cause of Death Registry and Cancer Registry. Multivariable Cox regression was used to calculate HRs with 95% CIs for mortality with adjustments for potential confounders.
Results We included 4758 participants with severe reflux symptoms and 51 381 participants without reflux symptoms, contributing 60 323 and 747 239 person-years at risk, respectively. Severe reflux was not associated with all-cause mortality, overall cancer-specific mortality or mortality in cancer of the head-and-neck or lung. However, for men with severe reflux a sixfold increase in oesophageal adenocarcinoma-specific mortality was found (HR 6.09, 95% CI 2.33 to 15.93) and the mortality rate was 0.27 per 1000 person-years. For women, the corresponding mortality was not significantly increased (HR 3.68, 95% CI 0.88 to 15.27) and the mortality rate was 0.05 per 1000 person-years.
Conclusions Individuals with severe reflux symptoms do not seem to have increased all-cause mortality or overall cancer-specific mortality. Although the absolute risk is small, individuals with severe reflux symptoms have a clearly increased oesophageal adenocarcinoma-specific mortality.
- ACID-RELATED DISEASES
- GASTROESOPHAGEAL REFLUX DISEASE
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Significance of this study
What is already known on this subject?
GORD is defined by troublesome symptoms of heartburn or regurgitation.
GORD is frequent in Western populations and the prevalence is increasing.
GORD is associated with several complications, including oesophageal adenocarcinoma and possibly cancers of the head-and-neck and lung.
What are the new findings?
Severe reflux symptoms were not associated with any increased all-cause mortality, overall cancer-specific mortality or head-and-neck and lung cancer-specific mortalities.
Severe reflux symptoms were associated with increased oesophageal adenocarcinoma-specific mortality.
As only 14 of 4758 individuals with severe reflux symptoms were diagnosed with oesophageal adenocarcinoma, the absolute risk is low.
How might it impact on clinical practice in the foreseeable future?
GORD can be considered a benign disorder with no increased all-cause mortality. However, the clinician should be aware of the clear association with oesophageal adenocarcinoma and oesophageal adenocarcinoma-specific mortality, and rapid endoscopy should be performed if suspected.
GORD is a public health concern that affects as many as 10%–30% of the adult population in Western countries and the prevalence is increasing.1 ,2 The main established risk factors for GORD are heredity, obesity and tobacco smoking.3–5 GORD is defined by troublesome symptoms of heartburn or regurgitation, and is associated with substantial reductions in health-related quality of life and coincides with several other conditions, including sleep problems, asthma and other respiratory disorders.6–9 Complications of GORD include oesophagitis, peptic strictures of the oesophagus, Barrett's oesophagus, and oesophageal and oesophagogastric junctional adenocarcinomas.10 ,11 Oesophageal and junctional adenocarcinomas are characterised by poor prognosis with a 5-year survival below 20%, increasing incidence and a male predominance.12–14 GORD is also associated with some extra-oesophageal cancers, including head-and-neck and lung cancers.15–17 Despite the fact that GORD is associated with all these conditions, few studies have examined whether GORD is associated with a reduced overall prognosis or increased risk of cancer-specific mortality. The results from the available literature are conflicting.18–20
As the risk of oesophageal adenocarcinoma is known to be increased in reflux, we expected to find increased mortality from oesophageal adenocarcinoma and, thereby, also increased overall cancer-specific and all-cause mortalities. Due to the association with head-and-neck and lung cancers, we also expected to find increased mortality from these cancers. The aim of this study was to test these hypotheses in a large and unselected cohort of individuals.
For the purpose of this study, data from the Norwegian population-based cohort study, the Nord-Trøndelag health study (HUNT), was used. All residents of Nord-Trøndelag county aged 20 years and older were invited to participate in three consecutive health surveys: HUNT1 (1 January 1984 to 28 February 1986), HUNT2 (1 August 1995 to 30 June 1997) and HUNT3 (1 October 2006 to 30 June 2008). In addition, a separate questionnaire was sent to non-participants after HUNT3 in 2009 (questionnaire for non-participants). HUNT includes questionnaires that cover a wide range of health-related information, including reflux symptoms, lifestyle factors and clinical measurements. Data on reflux symptoms were available in HUNT2, HUNT3 and the questionnaire for non-participants. Further information on data collection and design is available elsewhere.21 Follow-up started from the initiation of HUNT2 (1 August 1995) until the end of the study (31 December 2014), thus defining the study period. If an individual participated in both HUNT2 and HUNT3 or the questionnaire for non-participants, follow-up started at date of participation in HUNT2.
Follow-up involved linking the HUNT data to the Norwegian Cancer Registry and the Norwegian Cause of Death Registry, using the 11-digit national identity number assigned to each Norwegian resident. All deaths in Norway are registered in the Norwegian Cause of Death Registry, and the Cancer Registry of Norway has a high level of completeness (98.8% in 2001–2005).22 ,23 In addition, HUNT receives updated information on emigration from Statistics Norway every quarter. Participants diagnosed with any cancer before participation in HUNT were excluded.
The study exposure was severe reflux symptoms. In HUNT2, HUNT3 and the questionnaire for non-participants, the participants were asked ‘to what degree have you had heartburn or acid regurgitation in the last 12 months?’ and answered according to three alternatives: ‘no’, ‘minor’ or ‘severe’ complaints. Participants reporting severe complaints were defined as exposed, and those reporting no complaints as unexposed. This definition of severe reflux has been validated with excellent results in a previous study, showing that 95% of participants reporting severe reflux symptoms experience reflux symptoms at least once a week.24 Those reporting minor complaints were not included in this study. Individuals participating in both HUNT2 and HUNT3 or the questionnaire for non-participants and reporting different degrees of reflux symptoms (severe and never) in the different studies were excluded to avoid interchange in the exposure.
The study outcomes were all-cause mortality, overall cancer-specific mortality, oesophageal adenocarcinoma-specific mortality and mortality from head-and-neck or lung cancer.
From the Cause of Death Registry, information was gathered on the dates of death among the participants. All deaths among the HUNT participants, that is, independent of cause, were included in the calculations for all-cause mortality.
Overall cancer-specific mortality
From the Cancer Registry, information was gathered on the site of cancer based on the International Classification of Diseases (ICD)-7 codes, morphology based on ICD-O-3 codes and date of cancer diagnoses. We defined cancer deaths as deaths reported in the Cause of Death Registry as caused by cancer only for participants who had a cancer diagnosis registered in the Cancer Registry as well. Participants diagnosed with any cancer as the cause of death were included in the calculations for cancer-specific mortality.
Oesophageal adenocarcinoma-specific mortality
Participants with oesophageal adenocarcinoma as the cause of death reported in the Cause of Death Registry, or deaths occurring within 1 year from the cancer diagnosis in the Cancer Registry, regardless of the registered cause of death in the Cause of Death Registry, were included in the calculations for oesophageal adenocarcinoma-specific mortality. We also included oesophagogastric junctional adenocarcinomas in this outcome.
Mortality from selected extra-oesophageal cancer sites
The extra-oesophageal cancer sites included cancers of the head and neck (labial, lingual, salivary, oral, pharyngeal, nasosinusoidal, laryngeal cancer) and lung. Participants with any of these selected extra-oesophageal cancers as the cause of death reported in the Cause of Death Registry, or deaths occurring within 1 year of the cancer diagnosis in the Cancer Registry, regardless of registered cause of death in the Cause of Death Registry, were included in the calculations of extra-oesophageal cancer-specific mortality.
As potential confounders we selected age, body mass index (BMI), tobacco smoking, alcohol consumption, physical activity, education level, chronic obstructive pulmonary disease, cardiovascular diseases, diabetes and hypertension. Information on these factors was collected through both HUNT2 and HUNT3. Height and weight were objectively measured by trained personnel in HUNT2 and HUNT3.21 In the questionnaire for non-participants, height and weight were self-reported. BMI was calculated by dividing weight in kilograms by height in square metres (kg/m2) and categorised according to the WHO's classification: <18.5 (underweight), 18.5–25 (normal weight), 25–30 (overweight) or >30 (obese).25 The participant's tobacco smoking status was categorised as never, previous or current. Alcohol consumption was assessed by the number of occasions of consumption per month and categorised as less than weekly or at least weekly consumption. Physical activity was assessed by hours or occasions of physical activity per week. High physical activity was defined as at least 1 hour, or at least one occasion, of physical activity per week. In addition, participants who reported high levels of walking at work were categorised into the high physical activity group. Low physical activity was anything lower than these cut-offs for high activity. Educational level was categorised as 12 years and less or more than 12 years of formal education. The presence of comorbidities was based on self-reported questionnaires. Chronic obstructive pulmonary disease included chronic bronchitis, emphysema and cough with phlegm for periods of at least 3 months. In addition, participants reporting previous or current asthma who also reported previous or current smoking were defined as having chronic obstructive pulmonary disease. Cardiovascular disease included previous myocardial infarction, angina pectoris or stroke/brain haemorrhage. The presence of diabetes was reported by the participants. Those participants reporting previous or current use of medication for high blood pressure were defined as having hypertension.
Time at risk was defined from the date of the first participation in HUNT2, HUNT3 or the questionnaire for non-participants until date of death, emigration or the end of the study (31 December 2014), whichever came first. HRs with 95% CIs were calculated using multivariable Cox regression comparing the mortality among individuals reporting severe reflux symptoms with those reporting no reflux symptoms. All analyses were performed separate for each sex. The HRs were adjusted for age (continuous variable), BMI (<18.5, 18.5–25, 25–30 or >30), tobacco smoking status (never, previously or current), alcohol consumption (<weekly or ≥weekly), physical activity (high or low), education (≤12 years or >12 years), chronic obstructive pulmonary disease (yes or no), cardiovascular diseases (yes or no), diabetes (yes or no) and hypertension (yes or no). In addition, analyses were stratified by age (<40, 40–60 and >60 years) to evaluate effect modification.
The study has ethical approval through the Regional Committee for Medical and Health Research Ethics, Central Norway (2012/1290 4.2009.328), including additional approval of the present study (approved 02.11.2015). All participants in HUNT gave written informed consent when participating stating that their data could be used in future medical research, including linkage to other registries.
A flowchart showing all exclusions of individuals considered for participation is shown in figure 1. After exclusion of 750 individuals (1.3%) due to different degree of reflux symptoms reported in the different studies, 4758 individuals with severe reflux symptoms and 51 381 without reflux symptoms participated, contributing 60 323 and 747 239 person-years at risk, respectively. The average follow-up was 14.4 years. Baseline characteristics of the study participants are shown in table 1. The participants with reflux were older, had higher BMI, drank alcohol less frequently, were more physically active, less educated and had more comorbidity than those without reflux, while the groups had a more similar distribution of sex and tobacco smoking status (table 1). In total, 9093 deaths occurred in the study population. The number of deaths for each sex, outcome and reflux status is shown in table 2.
Reflux and all-cause mortality
The crude all-cause mortality was higher in women with reflux (HR 1.61, 95% CI 1.46 to 1.78), but no difference remained after adjustment for the selected confounders (HR 1.05, 95% CI 0.92 to 1.19) (table 2). Age was the main factor explaining the difference in the crude and adjusted mortality rates in women.
Reflux and overall cancer-specific mortality
The crude cancer-specific mortality of all cancer types was increased in women with reflux (HR 1.49, 95% CI 1.21 to 1.83), but after adjustment for age and other confounders this increase became attenuated and statistically non-significant (HR 1.11, 95% CI 0.87 to 1.42) (table 2).
Reflux and oesophageal adenocarcinoma-specific mortality
The oesophageal adenocarcinoma-specific mortality was higher among men with reflux than those without. A sixfold difference remained after adjustment for confounders (HR 6.09, 95% CI 2.33 to 15.93). For women with reflux, the crude oesophageal adenocarcinoma-specific mortality was increased (HR 5.67, 95% CI 1.78 to 18.10), but after adjustments the association attenuated and became statistically non-significant (HR 3.68, 95% CI 0.88 to 15.27) (table 2). No participants with severe reflux symptoms died of oesophageal squamous cell carcinoma, compared with 17 participants without reflux symptoms.
Reflux and mortality from head-and-neck and lung cancers
The head-and-neck and lung cancer-specific mortality was not associated with reflux (table 2).
Reflux and mortality stratified by age
Stratification by age categories did not substantially alter the overall results regarding all-cause mortality or mortality related to cancer in men. In women, reflux became associated with increased risk of oesophageal adenocarcinoma-specific mortality among the participants above 60 years of age (HR 10.49, 95% CI 1.99 to 55.27) (table 3).
In this study, severe reflux symptoms were not associated with any increase in all-cause mortality, overall cancer-specific mortality or head-and-neck and lung cancer-specific mortality, but only an increase in oesophageal adenocarcinoma-specific mortality.
Strengths of this study include its prospective and population-based design, which counteracts recall bias and selection bias. The population of Nord-Trøndelag County is representative of the Norwegian population as a whole,26 and therefore the results can be generalised to other Western populations. The data on reflux have been well validated against a more comprehensive assessment with excellent results.24 Cancer deaths were retrieved both from the Cancer Registry and the Cause of Death Registry to validate these data. The population studied was large and the time of follow-up was long, providing a robust statistical power.
In this study, we excluded the individuals reporting minor reflux symptoms. We believe that these individuals are a heterogeneous group, most without true reflux disease. This statement is based on two validation studies performed on the questionnaire used in the HUNT study. In these validation studies, we found that 95%–98% of the participants reporting severe reflux symptoms also reported at least weekly reflux symptoms, while only 25%–31% of the participants reporting minor reflux symptoms also reported at least weekly reflux symptoms.1 ,24 At least weekly reflux is considered the cut-off level for defining reflux disease according to the Montreal definition.6 We believe that the group of individuals reporting minor reflux symptoms mostly include individuals with physiological reflux or functional complaints and not individuals with true reflux disease. Thus, by excluding these, we are confident that the validity of the study is increased.
In the analyses, we dichotomised three of the covariables with large number of categories in the questionnaires, that is, alcohol consumption, physical activity and education, using common and previously used cut-off levels decided beforehand. This was done to maintain statistical power and to make the variables correspond well due to slight revisions of the questionnaires between the studies. We also did a sensitivity analyses with more categories of the covariables in the model, and the results remained virtually unchanged (data not shown).
The study has low rates of missing values among the participants (<5%), except for education (20%). As education was assessed in HUNT2 only, we have missing information on education among those participants only participating in HUNT3 or the questionnaire for non-participants. In Cox regression analyses, only ‘complete cases’ are analysed and participants with missing information are excluded. To assess the effect of missing data on education, we ran a sensitivity analysis using data from HUNT2 participants only. In this sensitivity analysis, missing for education was reduced to only 3.6%. However, the sensitivity analysis did not change the results (data not shown), meaning that the missing values did not affect the conclusion of the study.
The number of individuals (n=750) excluded from the analyses due to change in reported complaints with reflux disease between HUNT2 and HUNT3 or the questionnaire for non-participants was small (1.3%) compared with the total number of included participants (n=56 139) and should not have major influence on the results.
As mortality was the main outcome of this study, we excluded participants with a cancer diagnosis in the Cancer Registry, but without this cancer reported as the cause of death in the Cause of Death Registry. However, for oesophageal adenocarcinoma and head-and-neck and lung cancers we did still include these participants if they died within 1 year after the date of cancer diagnosis, as we believe that these deaths still could be related to these cancers as they are known to have a poor prognosis. This decision could overestimate the cancer-specific mortality of the respective cancers, but still reflux was not associated with head-and-neck and lung cancer-specific mortality.
The results of this study align with those from a smaller population-based cohort study from the USA, which found no difference in all-cause mortality between 115 individuals with daily and 2708 individuals without reflux symptoms.18 A cohort study from the UK found that patients with GORD (n=7159) had a 60% increased all-cause mortality within the first year of follow-up after inclusion, compared with patients without GORD (n=10 000), but no difference was seen for the remaining 4 years of follow-up.19 In our study, reflux was neither associated with all-cause mortality after 1 nor 5 years of follow-up (data not shown). Interpreting the results from the present study and the findings of previous studies indicate that reflux does not affect overall all-cause mortality.
The findings regarding cancer-specific mortality are different from an Iranian population-based cohort study reporting that participants with severe reflux symptoms (n=172) had a 48% increase in cancer-specific mortality compared with participants without reflux symptoms (n=1240), while no association was found for oesophageal cancer.20 However, the Iranian study could not separate oesophageal adenocarcinoma from squamous cell carcinoma, and most oesophageal cancers in Iran are squamous cell carcinomas without any association with reflux.10 Moreover, differences in study design, living conditions and ethnicity, as well as chance, may explain the divergent findings.
Our study confirms the lack of association between reflux and oesophageal squamous cell carcinomas as there were no deaths due to oesophageal squamous cell carcinoma among the participants with severe reflux symptoms, while there were 17 deaths due to oesophageal squamous cell carcinoma among those without reflux symptoms. Reflux was also, as expected, not associated with gastric (non-cardia) cancer-specific mortality (data not shown).
The increased oesophageal adenocarcinoma-related mortality is expected, given the well established and strong association between GORD and oesophageal adenocarcinoma incidence.10 ,12 Yet, only 14 of the 4758 individuals with severe reflux symptoms were diagnosed with an oesophageal adenocarcinoma, which emphasises the fact that the absolute risk is low even in individuals with GORD.29 This is, to the best of our knowledge, the first study examining the mortality related to head-and-neck and lung cancers, and no association was found.
In conclusion, this prospective and population-based cohort study with a large sample size and adjustment for confounding factors indicates that severe reflux symptoms do not entail any increased all-cause mortality or overall cancer-specific mortality, although an increase in oesophageal adenocarcinoma-specific mortality was found.
The Nord-Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine, NTNU, Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Health Authority, and the Norwegian Institute of Public Health. The study has used data from the Cancer Registry of Norway and the Norwegian Cause of Death Registry. The interpretation and reporting of these data are the sole responsibility of the authors, and no endorsement by the Cancer Registry of Norway or the Norwegian Cause of Death Registry is intended nor should be inferred.
Contributors EN-J contributed to the study concept and design, statistical analyses and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, approved the final version of the manuscript and is guarantor for the overall content of the manuscript. EG-V contributed to the study concept and design, statistical analyses and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content and approved the final version of the manuscript. KW contributed to the statistical analysis and interpretation of data, critical revision of the manuscript for important intellectual content and approved the final version of the manuscript. JL contributed to the study concept and design, critical revision of the manuscript for important intellectual content and approved the final version of the manuscript.
Funding EN-J, KW and JL are funded by the Swedish Research Council.
Competing interests None declared.
Ethics approval The Regional Committee for Medical and Health Research Ethics, Central Norway.
Provenance and peer review Not commissioned; externally peer reviewed.
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