Discussion
In this prospective population-based cohort of Swedish men and women followed up for 12 years, there was a significant inverse linear dose–response association between vegetable consumption, but not fruit consumption, and risk of non-gallstone-related acute pancreatitis. The risk reduction seemed to be more pronounced among alcohol drinkers and among overweight participants.
Reactive oxygen and nitrogen species, although unable to induce the pathological process, are important in the pathogenesis of acute pancreatitis. Intake of dietary antioxidants can hypothetically create an optimal redox balance and diminish the effect of oxidative stress in the pancreas. The most likely mechanism whereby vegetables may protect against the development of non-gallstone-related acute pancreatitis is therefore the high content of antioxidants, for example, vitamin C and β-carotene. Of clinical interest are the observed associations when stratifying the analysis by alcohol consumption and BMI. The reduction in the risk of the disease seemed to be more pronounced among participants with a daily alcohol consumption of >1 drink as compared with those consuming less alcohol. Similarly, the inverse association appeared to be stronger among overweight and obese participants than among those with normal weight. Excessive alcohol consumption as well as overweight and obesity are factors associated with systemic oxidative stress. Alcohol has also been shown to increase oxidative stress in the pancreas. Thus, the inverse association between vegetables and the risk of non-gallstone-related acute pancreatitis might be stronger among those with underlying oxidative stress. Even though smoking is another factor associated with systemic oxidative stress and inflammatory changes in the pancreas, the RRs were similar when stratifying the analysis by smoking status. We acknowledge however the limited number of cases available in our study when assessing interactions and performing subgroup analyses.
Since both vegetables and fruit are rich in antioxidants, the lack of inverse association between fruit and risk of non-gallstone-related acute pancreatitis was unexpected. One case-control study from South Africa has previously observed an inverse association between fruit and risk of acute pancreatitis. However, that study was small (n=30 cases with acute pancreatitis) and with a non-quantitative assessment of dietary consumption (adequate vs inadequate). One possible explanation to our findings might be the content of fructose in fruit. Several experimental studies on animals have investigated the association between fructose and oxidative stress. Administration of fructose-rich diets to rats has led to an increase of oxidative markers, for example, indicators for lipid peroxidation and protein oxidation. In addition, as a sign of direct effect of fructose on the redox balance, treatment with antioxidants has decreased the generation of reactive oxygen species among fructose-fed rats. Alteration of the oxidative status by fructose might therefore counteract the potential beneficiary effects provided by antioxidants in fruit.
The recommended combined consumption of vegetables and fruit is five servings per day in most countries. The findings from our study suggest that a vegetable consumption in line with the general recommendation (the median value in the highest quintile of vegetable consumption was 4.6 servings per day) can be protective against the development of non-gallstone-related acute pancreatitis. Although our results for vegetables may indicate an important role of redox balance in the primary prevention of non-gallstone-related acute pancreatitis, the treatment with high doses of mixed antioxidants (eg, n-acetylcysteine, vitamin C and selenium) as a part of the clinical management of acute pancreatitis has not significantly decreased complications or mortality of the disease. However, antioxidants may under certain conditions, for example, in high doses, act as pro-oxidants. It is therefore theoretically possible that treatment with antioxidants may fail to be beneficial during an attack of acute pancreatitis.
The strengths of our study are the population-based prospective design, large sample size and nearly complete follow-up of the study population by linkage to different registers. The diagnosis of acute pancreatitis has also been shown to have a high validity in the Swedish Patient Register. An additional strength is the detailed information on diet and potential confounders. However, the present study also has some limitations. The use of self-administered food-frequency questionnaires is related to some misclassification of vegetable and fruit consumption, but such misclassification is expected to be non-differential with respect to the disease and should most likely underestimate any true association. Moreover, we cannot rule out the possibility that some of the participants with acute pancreatitis might have had chronic pancreatitis that clinically presented itself as acute pancreatitis. However, by excluding those with a previous history of exocrine pancreatic disease this possibility was reduced. Also, the definition of gallstone-related—and non-gallstone-related—acute pancreatitis is in the focus of an ongoing discussion. Finally, we could not adjust our analyses for the occurrence of other known risk factors of non-gallstone-related acute pancreatitis: for example, cystic fibrosis, hypercalcaemia, hypertriglycaemia and drug-induced pancreatitis. The potential residual confounding by these factors is however unlikely to fully explain the magnitude of the observed associations in this study. These comorbidities explain only a small amount of the cases with non-gallstone-related acute pancreatitis, and the prevalence of cystic fibrosis in the study cohort was 5 per 100 000 individuals at the start of follow-up.
In conclusion, results from this prospective cohort of men and women show that a high vegetable consumption may reduce the risk of non-gallstone-related acute pancreatitis. The inverse association seems to be stronger among participants consuming >1 drink of alcohol per day and among overweight participants. Our findings, if confirmed by other studies, indicate a potential benefit of increasing the consumption of vegetables for the prevention of non-gallstone-related acute pancreatitis.