Oily fish and asthma - a fishy story?
Further studies are required before claims can be made of a beneficial effect of oily fish consumption on asthma
Interest in the possible health benefits of dietary fish lipids followed observations that populations with a high dietary intake of fish, such as Greenland Inuit and the Japanese, had low incidences of atherosclerotic disorders and of inflammatory conditions such as rheumatoid arthritis. Our recent understanding of asthma as a chronic inflammatory airway disease has led to speculation that a diet rich in fish oil may also ameliorate asthma.
The potential anti-inflammatory effect of fish oil stems from its active ingredient, eicosapentaenoic acid (EPA), which is a competitive substrate with arachidonic acid for the generation of inflammatory mediators. The derivatives of arachidonic acid (an n-6 fatty acid) are leukotriene B4 (LTB4), a potent neutrophil chemoattractant and pro- inflammatory mediator, and the cysteinyl series of leukotrienes (LTC4, LTD4 and LTE4), which produce potent smooth muscle contraction and bronchoconstriction. In contrast, EPA (an n-3 fatty acid), as well as inhibiting arachidonic acid metabolism, is a substrate for the less active prostanoids (e.g., thromboxane A3) and leukotrienes (e.g., LTB5), and so has the potential to reduce airway inflammation and reverse bronchoconstriction.
As the most profound anti-inflammatory actions of fish oil are on neutrophil function and mediator generation, it is not surprising that clinical trials of dietary fish oil have been beneficial in diseases where there is a neutrophilic inflammation, such as rheumatoid arthritis, psoriasis, cystic fibrosis and inflammatory bowel disease. However, in asthma the role of neutrophils is much less certain. Eosinophils and mast cells are thought to be the predominant effector cells in asthma (through the release of mediators), with T lymphocytes, macrophages and, possibly, mast cells having initiating and immunomodulatory roles through cytokine secretion.
Placebo-controlled interventional studies of high dose fish oil supplementation in patients with asthma have been disappointing. Early short term trials (eight weeks) of up to 4 g/day of EPA in severe asthmatics showed no clinical benefit, despite demonstrating profound suppression of neutrophil chemotaxis and mediator generation.1 In a study in aspirin-intolerant subjects asthma control worsened after six weeks of 3 g/day of EPA, 2 consistent with the known aspirin-like effect of cyclooxygenase inhibition by EPA. Further studies in milder asthmatics with 3.2 g/day for 10 weeks showed no benefit in either clinical symptoms or bronchial hyperresponsiveness,3 despite demonstrating attenuation of allergen-induced late-phase bronchoconstriction induced in the laboratory.4 A more prolonged trial for six months with 3.2 g/day of EPA also showed no clinical benefit in patients with pollen-induced asthma and seasonal hayfever.5
These disappointing results are consistent with in-vitro evidence that EPA does not inhibit eosinophils and mast cells. In contrast to its dampening effect on neutrophils, EPA incubated with cultured murine mast cells produced a marked increase in production of platelet-activating factor, without an effect on histamine release.6 Similarly, stimulated human eosinophils incubated with EPA generated significantly greater amounts of leukotrienes than those incubated with arachidonic acid.7 Furthermore, in asthma there is a complex interaction between cells, cytokines, nerves and lipid and other mediators. Although of the lipid mediators leukotrienes may have the most influential role in asthma, modulating any one group of inflammatory mediators alone may not be sufficient to produce clinical improvement.
The only interventional study which has shown positive results was a small placebo-controlled trial of low-dose EPA (1 g/day) for 12 months in 12 adult asthmatic subjects (six taking fish oil and six taking placebo). After nine months a small but significant improvement was found in forced expiratory volume at one second (FEV1).8 However, no details were given of concurrent medication use or assessment of compliance with therapy by leukocyte membrane phospholipid analysis, and there have been no follow-up data since 1991.
The question of fish diet and respiratory health has also been investigated from an epidemiological perspective in recent American studies. In a survey of 2526 adult subjects aged 30-70 years, the first National Health and Nutrition Survey found eating fish more than once a week, compared with less than once a week, was associated with a higher level of lung function. However, only 2.9% of subjects in this survey were asthmatic, so no conclusion could be drawn about the effect of fish consumption on asthma.9 The Atherosclerosis Risk in Communities (ARIC) study surveyed 8960 adult current and former smokers10 and reported that a high dietary intake of n-3 fatty acids was inversely related to the risk of chronic obstructive pulmonary disease (COPD). This apparent protective effect is biologically plausible as neutrophilic inflammation is a feature of COPD. The Nurses' Health Study, possibly the largest prospective study of its type, reporting the incidence of adult-onset asthma in 77 866 women aged 34-68 years, found no relationship between dietary intake of fatty acids and the incidence of doctor-diagnosed asthma over a 10-year period.11
With this background, what interpretation can be put on the study by Hodge et al. in this issue of the Journal (page 137)? The novel aspects of this epidemiological survey are that the study population consisted of Australian children aged 8-11, and that the diagnosis of asthma was based both on symptoms and measurement of bronchial hyperresponsiveness. The investigators found an inverse relationship between weekly oily fish intake and prevalence of asthma in 574 schoolchildren. A number of salient points may be made. Firstly, the investigators previously reported an inverse relationship between weekly total fish intake and asthma, which is not evident in this study. This may reflect the inherent variability of food frequency questionnaire data or the different sample sizes of the two studies, but it does raise doubts about the primary hypothesis being tested. Secondly, the estimated mean intake of EPA from a weekly serve of fish10 is about 0.2-0.8 g, which is much lower than the amount that would be expected to have anti-inflammatory effects on leukocyte mediator and cytokine generation. It is possible that it is not the oil in the fish per se but some other dietary or social component associated with families who eat fish which is responsible for these results. Thirdly, a much larger prospective study in adults did not find a similar relationship between dietary fish intake and asthma prevalence.11 Can this discrepancy be explained by subtle effects of low-dose fish oil on the immunological development of asthma in childhood, which are no longer relevant in adulthood? There is currently insufficient understanding of the mechanisms involved to put forward a biologically plausible hypothesis. Finally, the study of Hodge et al. is a cross-sectional study, and thus cannot establish a temporal relationship between oily fish intake and asthma. Nevertheless, these are very interesting data but they need to be confirmed in larger studies.
Placebo-controlled prospective intervention studies with dietary manipulation for prolonged periods in childhood are also required before any claim can be substantiated. Until then, unwarranted speculation about the relationship between dietary fats and asthma12 should be avoided as this may have a negative impact on other health outcomes, cause even more confusion about diet and health in the general population and undermine an evidence-based approach to public health initiatives.
Francis C K Thien
Rosalie K Woods
E Haydn Walters
Department of Respiratory Medicine, Alfred Healthcare Group
(©MJA 1996; 164: 135-136)
- Kirsch CM, Payan DG, Wong MYS, et al. Effect of eicosapentaenoic acid in asthma. Clin Allergy 1988; 18: 177-187.
- Picado C, Castillo JA, Schinca N, et al. Effects of a fish oil enriched diet on aspirin intolerant asthmatic patients: a pilot study. Thorax 1988; 43: 93-97.
- Arm JP, Horton CE, Mencia-Huerta J-M, et al. Effect of dietary supplementation with fish oil lipids on mild asthma. Thorax 1988; 43: 84-92.
- Arm JP, Horton CE, Spur BW, et al. The effects of dietary supplementation with fish oil lipids on the airways response to inhaled allergen in bronchial asthma. Am Rev Respir Dis 1989; 139: 1395-1400.
- Thien FCK, Mencia-Huerta J-M, Lee TH. Dietary fish oil effects on seasonal hay fever and asthma in pollen-sensitive subjects. Am Rev Respir Dis 1993; 147: 1138-1143.
- Triggiani M, Connell TR, Chilton FH. Evidence that increasing the cellular content of eicosapentaenoic acid does not reduce the biosynthesis of platelet-activating factor. J Immunol 1990; 145: 2241-2248.
- Thien FCK, Hallsworth MP, Soh C, Lee TH. Effects of exogenous eicosapentaenoic acid on generation of leukotriene C4 and leukotriene C5 by calcium ionophore-activated human eosinophils in vitro. J Immunol 1993; 150: 3546-3552.
- Dry J, Vincent D. Effect of a fish oil diet on asthma: results of a 1-year double-blind study. Int Arch Allergy Appl Immunol 1991; 95: 156-157.
- Schwartz J, Weiss ST. The relationship of dietary fish intake to level of pulmonary function in the first National Health and Nutrition Survey (NHANES I). Eur Resp J 1994; 7: 1821-1824.
- Shahar E, Folsom AR, Melnick SL, et al. Dietary n-3 polyunsaturated fatty acids and smoking-related chronic obstructive pulmonary disease. N Engl J Med 1994; 331: 228-233.
- Troisi RJ, Willett WC, Weiss ST, et al. A prospective study of diet and adult-onset asthma. Am J Respir Crit Care Med 1995; 151: 1401-1408.
- Hodge L, Peat JK, Salome C. Increased consumption of polyunsaturated oils may be a cause of increased prevalence of childhood asthma. Aust N Z J Med 1994; 24: 727.
(©MJA 1996; 164: 135-136)
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