- C.E. Lenox1,* and
- J.E. Bauer2
Article first published online: 16 JAN 2013
Tables and references can be found at: Potential Adverse Effects of Omega3 Fatty Acids in Dogs and Cats - Lenox - 2013 - Journal of Veterinary Internal Medicine - Wiley Online Library
Quote:
Abstract
Fish oil omega-3 fatty acids, mainly eicosapentaenoic acid and docosahexaenoic acid, are used in the management of several diseases in companion animal medicine, many of which are inflammatory in nature. This review describes metabolic differences among omega-3 fatty acids and outlines potential adverse effects that may occur with their supplementation in dogs and cats with a special focus on omega-3 fatty acids from fish oil. Important potential adverse effects of omega-3 fatty acid supplementation include altered platelet function, gastrointestinal adverse effects, detrimental effects on wound healing, lipid peroxidation, potential for nutrient excess and toxin exposure, weight gain, altered immune function, effects on glycemic control and insulin sensitivity, and nutrient-drug interactions.
Abbreviations
AAarachidonic acid
ALAalpha-linolenic acid
DHAdocosahexaenoic acid
DTHdelayed-type hypersensitivity
EPAeicosapentaenoic acid
LAlinoleic acid
n-6:n-3dietary omega-6 to omega-3 ratio
PUFA(s)polyunsaturated fatty acid(s)
Fish oil omega-3 fatty acids have been investigated for benefits in management of several diseases and often are recommended for management of clinical problems including neoplasia,[1] dermatologic disease,[2-4] hyperlipidemia,[5, 6] cardiovascular disease,[7, 8]renal disease,[9, 10] gastrointestinal disease,[11, 12] and orthopedic disease.[13-16] Because omega-3 fatty acids are nutrients used in the management of disease, they are considered nutraceuticals. The term nutraceutical refers to a nutrient that has characteristics of a drug.[17] Omega-3 fatty acids, however, are different from drugs because relatively high doses of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are required for the treatment of disease as compared to most drugs, because most commercial pet foods contain a source of omega-3 fatty acids, and because DHA and possibly EPA are required nutrients for some lifestages (especially during growth and development). Like all drugs and dietary supplements, there is potential for adverse effects with usage of omega-3 fatty acids, especially when diets are supplemented with them or when they are present in diets in large amounts.
Currently, there are few commercial pet foods with EPA and DHA concentrations adequate for treatment of disease. Joint diets, renal diets, and diets for dermatologic conditions typically contain more omega-3 fatty acids than maintenance diets, but even therapeutic diets may not supply enough omega-3 fatty acids for treatment of disease. Target ranges for EPA and DHA vary quite widely for different conditions, but typically fall between 50 and 220 mg/kg body weight. The higher dosages often are used to lower serum triglyceride concentrations in patients with hypertriglyceridemia, whereas lower dosages are more commonly used for inflammatory conditions, renal disease, and cardiac disease. Commercial diets containing omega-3 fatty acids typically provide less EPA and DHA than desirable and may be advertised as containing omega-3 fatty acids but contain flaxseed or canola oil (rich in alpha-linolenic acid [ALA]) instead of fish oil. A discussion of the benefits of EPA and DHA as compared to ALA is included in this review. Because of the lower concentrations of EPA and DHA as compared with other omega-3 fatty acids and target concentrations, the authors frequently recommend supplementing EPA and DHA in addition to using a diet containing omega-3 fatty acids.
The purpose of this review is to outline a number of potential adverse effects $#@!ociated with use of omega-3 fatty acids, with special focus on adverse effects of EPA and DHA supplementation. This topic was reviewed by Hall in [18], but the increase in research in the area in both humans and animals, the increase in clinical recommendations for omega-3 fatty acid supplementation, and the increase in commercial pet foods containing EPA and DHA make the topic important to revisit. First, basic concepts of fatty acid metabolism are discussed. Potential adverse effects that are discussed include altered platelet function, gastrointestinal adverse effects, detrimental effects on wound healing, lipid peroxidation, potential for nutrient excess and toxin exposure, weight gain, altered immune function, effects on glycemic control and insulin sensitivity, and nutrient-drug interactions. These adverse effects are summarized in both general and specific manners in Table 1.
Basic Concepts of Fatty Acid Metabolism
Dietary fatty acids can be classified as saturated (containing no double bonds), monounsaturated (containing 1 double bond), or polyunsaturated (containing ≥2 double bonds). Polyunsaturated fatty acids (PUFAs) can be classified further as omega-6 or omega-3 depending on the location of the 1st double bond from the methyl (omega) end of the molecule. Fatty acids frequently are described using a shorthand notation based on the number of carbons in the fatty acid chain, the number of double bonds in the fatty acid, and whether the fatty acid is omega-6 or omega-3, if applicable. For example, linoleic acid (LA) contains 18 carbons and 2 double bonds with the 1st double bond occurring after the 6th carbon atom from the methyl end of the structure and designated as 18:2n-6.
Fish oil omega-3 fatty acids are long-chain PUFAs and include EPA (20:5n-3) and DHA (22:6n-3). These fatty acids are characterized by 5 or 6 double bonds with the 1st one occurring between the 3rd and 4th carbon from the methyl end of the fatty acid chain. Theoretically, EPA and DHA can be derived from another omega-3 fatty acid, ALA (18:3n-3). ALA is found in plant products such as flaxseed oil and can be converted to EPA and DHA by desaturation (addition of double bonds to the fatty acid chain) and elongation (addition of an even number of carbons to the fatty acid chain). However, in mammals, ALA is not efficiently converted to EPA and DHA. The conversion rate of ALA to EPA and DHA is believed to be <10% in humans,[19, 20] and also is believed to be rather limited in dogs[21, 22] and cats.[23, 24] Therefore, when supplementing omega-3 fatty acids, fish oil is a more potent and efficient source of EPA and DHA as compared with products rich in ALA such as flaxseed, linseed, or canola oil. Supplementation of ALA does have benefits, especially in management of dermatologic disease,[2] but different omega-3 fatty acids have different effects on the body and on disease.
Fish oil omega-3 fatty acids are used for management of the aforementioned diseases primarily because of their anti-inflammatory properties. However, inflammation does not play a major role in the pathogenesis of all of these disorders (eg, some cardiovascular diseases, hyperlipidemia). In these instances, omega-3 fatty acids are believed to have beneficial effects in addition to their role in decreasing inflammation. For example, omega-3 fatty acids are thought to have antitumor effects[1] and effects on blood lipid concentrations,[5, 6, 25] and improved receptor and ion channel functions.[26, 27]
Omega-6 fatty acids have a double bond between the 6th and 7th carbon from the omega-end of the fatty acid molecule. One of the omega-6 fatty acids is LA, which is considered essential in all mammals because of lack of the enzyme needed for its synthesis.[24, 28] Linoleic acid is efficiently converted to arachidonic acid (AA, 20:4n-6) in dogs, but not in cats. Delta-6 desaturase regulates the 1st step in the desaturation of essential fatty acids; it adds a double bond between the 6th and 7th carbons from the carboxyl end of the fatty acid.[29] Cats have a dietary requirement for AA because of limited delta-6 desaturase activity.[23]
Lipid metabolites, also called eicosanoids, are derived from long-chain PUFAs and include prostaglandins and leukotrienes. Eicosanoids can act as inflammatory mediators.[30] Arachidonic acid in plasma membranes serves as a substrate for production of eicosanoids of the 2-series of prostaglandins and 4-series of leukotrienes by the action of cyclooxygenases and lipooxygenases.[15, 16, 31] In contrast, EPA and DHA in plasma membranes result in production of different eicosanoids (mainly the 3-series of prostaglandins and 5-series of leukotrienes) that are less proinflammatory compared with those derived from AA.[15, 16, 31] The production of these less proinflammatory eicosanoids results in EPA and DHA being characterized as anti-inflammatory. These effects can be observed after dietary supplementation with omega-3 fatty acids and after incorporation into plasma membranes of tissues.[32]
When fish oil omega-3 fatty acids are administered, they can be given as a supplement separate from the diet (such as a liquid or capsule containing fish oil) or as part of the animal's diet. The amount of omega-3 fatty acids supplemented can be expressed as an absolute amount (total milligrams of EPA and DHA), a milligram per kilogram dosage, or as a dietary omega-6 to omega-3 (n-6:n-3) ratio. The total n-6:n-3 should be used with caution, because it does not reflect the total amount of omega-3 fatty acids present in the diet or the type of omega-3 fatty acids present.
The total n-6:n-3 ratio has been used extensively in reports because there is competition between LA and ALA for enzymes that desaturate and elongate these fatty acids.[33] However, this ratio should be used with care because, in most instances, it is calculated using total omega-3 fatty acids (ALA, EPA, and DHA). The use of the total omega-3 concentration is not bioequivalent to the EPA and DHA concentration, because of the poor conversion of ALA to EPA and DHA and because ALA does not have the same biologic effects as the long-chain omega-3 PUFAs. Consequently, many researchers consider the total intake of the individual omega-6 and omega-3 fatty acids to be more important than their ratio.[33, 34] The n-6:n-3 ratio can be altered in several ways. The omega-3 fatty acid concentration could be increased, decreased, or unchanged resulting in either an increase or decrease in the n-6:n-3 ratio. Waldron et al found that in dogs fed 2 different diets with the same n-6:n-3 ratio but with different sources of omega-3 fatty acids (linseed oil versus menhaden fish oil), neutrophil function was affected differently.[35] Thus, the type and amount of omega-3 fatty acids are likely more influential compared with the total n-6:n-3 ratio.
Although the n-6:n-3 ratio has been used primarily in many of the studies described in this review, to the extent possible and when reported, it will be pointed out when long-chain omega-3 PUFAs were used, when an unknown combination of ALA and long-chain omega-3 PUFAs was used, and how the ratio was calculated. Many of these adverse effects are theoretical at this time. The fact that many of the studies cited used the n-6:n-3 ratio as opposed to specifying the total omega-3 fatty acid dosage or EPA and DHA concentration make the results of many of the studies difficult to interpret with respect to actual amounts used.
Potential Adverse Effects of Omega-3 Fatty Acids in Dogs and Cats
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