Potential Adverse Effects Of Long-term Consumption Of Fatty Acids

Vol.18, No. 8

August 1996

V

Continuing Education Article

FOCAL POINT ★ The long-term effects of (n-3) fatty acid supplementation for companion animals have not been investigated.

KEY FACTS ■ The risk of bleeding after prolonged intake of (n-3) fatty acids seems to be very low. ■ A high intake of (n-3) fatty acids could lead to impairment of linoleic-acid metabolism and a deficit of its fatty-acid derivatives, which may not be risk free. ■ A possible adverse effect of high levels of dietary (n-3) fatty acids is that their accumulation in tissue makes the tissue vulnerable to lipid peroxidation. ■ Whether the observed decreases in immune and inflammatory responses are sufficient to compromise normal host defenses is unknown.

Potential Adverse Effects of Long-Term Consumption of (n-3) Fatty Acids* Oregon State University

Jean A. Hall, DVM, PhD

T

he potential benefits of dietary supplementation with (n-3) (also called ω-3) fatty acids have aroused great interest. As a result, various pet foods and fatty acid supplements rich in (n-3) fatty acids are currently marketed for administration to dogs and cats. However, long-term studies of the effects of dietary supplementation with (n-3) fatty acids in these species are lacking. Potential toxic or adverse effects of long-term (n-3) fatty acid consumption should not be ignored but should be investigated in conjunction with ongoing research to determine whether diseased dogs or cats will benefit from the use of these agents.

POLYUNSATURATED FATTY ACIDS Overview Fatty acids are classified as saturated, monounsaturated, or polyunsaturated on the basis of the number of double bonds in the fatty acid’s carbon chain. Each class of fatty acids has different properties and unique biologic characteristics.1,2 Polyunsaturated fatty acids are named according to the position of the first double bond—counting from the methyl end of the molecule (Figure 1). The two most important series of polyunsaturated fatty acids are the (n-3) series (which have the first double bond located at the third carbon atom) and the *Editor’s Note: This article, which was derived in part from a presentation at the Thirteenth ACVIM Veterinary Medical Forum, is presented to give the reader an overview of potential adverse effects of (n-3) fatty acid supplementation. Although these products appear to be very safe as currently used, their long-term effects in companion animals have not been studied. Most of the information regarding adverse effects is taken from studies of humans. A second article describing the benefits of fatty acid supplementation in small animals will be presented in an upcoming issue of Compendium. As with all new therapies, practitioners must weigh the costs and benefits before making recommendations.

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(n-6) series (which have the derived from arachidonic Linoleic acid 18:2 (n-6) first double bond located at acid. the sixth carbon atom). Although no conversion COOH Both linoleic acid and αbetween (n-3) and (n-6) selinolenic acid, which are ries of fatty acids takes the precursors of the (n-6) place, inhibition and comCH3 and (n-3) series, respectivepetition between fatty acids ly, are essential fatty acids of different series have been because mammals cannot demonstrated.4–6 For examα-Linolenic acid 18:3 (n-3) ple, the metabolism of αsynthesize them from other linolenic acid is inhibited series of fatty acids. Mamby members of the linoleicmals lack the enzymes to acid family: arachidonic introduce double bonds at acid, γ-linolenic acid, and carbon atoms before the COOH CH3 linoleic acid. The competininth carbon atom in the fatty acid chain (counting Figure 1—Polyunsaturated fatty acids of the (n-6) series tive equilibrium between from the methyl end). (linoleic acid 18:2 [n-6]) and of the (n-3) series (α-linolenic linoleate and linolenate can Therefore, these essential acid 18:3 [n-3]). The number of carbon atoms is listed be- be displaced in either direcfatty acids must be supplied fore the colon and the number of double bonds after the tion, and the fatty acid favored in the competition in the diet. Subsequent de- colon. depends on the relative levsaturation and elongation els of those fatty acids in proceed only toward the the diet.6 An excess of (n-6) fatty acids reduces the carboxyl terminus of the fatty acid. metabolism of α-linolenic acid, thus possibly leading to In general, fatty acids from both series can be elona deficit of its metabolites, including eicosapentaenoic gated and desaturated. Cats, however, have reduced ∆6 desaturase and therefore cannot adequately convert acid. However, the (n-3) fatty acids are much more eflinoleic acid to arachidonic acid. Thus, arachidonic fective in inhibiting (n-6) fatty acid metabolism than acid and linoleic acid must be supplied by the cat’s vice versa.4 3 diet. The elongation (increase in the number of carbon Sources Various diets and nutritional supplements are curatoms) and desaturation (increase in the number of rently marketed as sources of (n-3) fatty acids for comdouble bonds) of linoleic acid and α-linolenic acid are catalyzed by the same enzymes (Figure 2). However, inpanion animals. The fatty acid ratios of commercial terconversion between (n-3) fatty acids and (n-6) fatty dog foods vary widely, depending on the source of fat. acids is impossible because elongation and desaturation Diets containing safflower oil or corn oil are likely to be occur only toward the carboxyl terminus of the fatty high in (n-6) fatty acids and to have a ratio of (n-6) to acid. (n-3) greater than 30:1. Also, various (n-3) fatty acid Arachidonic acid (which is derived from the [n-6] supplements for human use are available over the fatty acid linoleic acid) and eicosapentaenoic acid counter. (which is derived from the [n-3] fatty acid α-linolenic (N-3) FATTY ACID SUPPLEMENTATION acid) are both fundamental components of cytoplasmic Potential Clinical Benefits membranes. Further metabolism of these fatty acids Dietary supplementation with (n-3) fatty acids may leads to the generation of eicosanoids (Figure 3). produce desirable clinical effects in dogs or cats with Prostaglandins, thromboxanes, and leukotrienes are all various diseases.2,7–9 In addition, extrapolation from derived from the metabolism of (n-3) and (n-6) fatty studies of animal models and human trials indicates acids through reactions involving cyclooxygenase and that these fatty acids have the potential to yield various lipoxygenase enzymes. clinical benefits (see the box). Some of the potential Eicosanoids are important mediators of cellular reacbenefits for cancer patients relate to the ability of (n-3) tions. The eicosanoids derived from arachidonic acid fatty acids to decrease production of certain cytokines and eicosapentaenoic acid have different biologic efthat mediate cancer cachexia. fects. For example, the eicosanoids that are derived Because of their ability to modify eicosanoid producfrom eicosapentaenoic acid are in general much less potion, (n-3) fatty acids have the potential to alter functent inducers of inflammation than are the eicosanoids ARACHIDONIC ACID ■ EICOSAPENTAENOIC ACID ■ FATTY ACID RATIOS

The Compendium August 1996

Small Animal

(n-6) Series

(n-3) Series

Linoleic acid 18:2 (n-6)

α-Linolenic acid 18:3 (n-3) ∆ 6 Desaturase (desaturation)

γ-Linolenic acid 18:3 (n-6)

Stearidonic acid 18:4 (n-3) Elongase (elongation)

Dihomo-γ-linolenic acid 20:3 (n-6)

Eicosatetraenoic acid 20:4 (n-3) ∆ 5 Desaturase (desaturation) Eicosapentaenoic acid 20:5 (n-3)

Arachidonic acid 20:4 (n-6)

compared with the response to fish-oil consumption or to a specific dose of (n-3) fatty acids. In addition, there are inherent problems in extrapolating from other species to dogs and cats. The effects of dietary supplementation with (n-3) fatty acids for dogs and cats have not been well studied. Experimental data on the correct dosage of (n-3) fatty acids or the best ratio of (n6) to (n-3) fatty acids in the diet for maximizing benefits and minimizing side effects are few. Nevertheless, the following safety issues should be considered before longterm dietary supplementation with (n-3) fatty acids is recommended.

Contamination of Sources Fish oil, which is a major dietary source of (n-3) fatty acids, may contain heavy 22:5 (n-3) 22:4 (n-6) metals and organic chemicals that were concentrated ∆ 4 Desaturase in the lipids of fish caught (desaturation) in waters contaminated with Docosahexaenoic acid industrial by-products (e.g., 22:5 (n-6) dioxin and dibenzofurans).18 22:6 (n-3) These findings do not warFigure 2—Fatty acid biosynthesis: the elongation and desaturation of the (n-6) fatty acid rant restriction of the consumption of fish oil but linoleic acid and the (n-3) fatty acid α-linolenic acid. should serve as a reminder of potential food contamition or disease processes in many different body sysnation by these toxic substances. Heavy metals and pestems (e.g., the gastrointestinal and renal systems) that ticides may be removed during the processing of fishare influenced by prostaglandins.13–17 Whether dietary oil concentrates.19 Veterinarians prescribing (n-3) fatty supplementation with (n-3) fatty acids will be benefiacid supplements should ask commercial suppliers if cial in the treatment of the disease processes discussed the products are free of contaminants. Most manufacremains to be seen. turers carefully screen their oils to ensure that they do not contain unwanted substances. Potential Adverse Effects Many of the studies cited below have been conducted Hemostatic Abnormalities Many studies have addressed the concern about an with research animals or with human patients. The increased risk of bleeding after prolonged intake of (ndosages used, the duration of the feeding trials, and 3) fatty acids,20 but the risk seems to be very low.21 Prothus the biologic responses often vary between studies. thrombin time, activated partial thromboplastin time, For example, the response to fish consumption may be

Elongase (elongation)

DIOXIN ■ DIBENZOFURANS ■ HEAVY METALS ■ PESTICIDES

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and plasma levels of thrombin-antithrombin complexes are usually unaltered by (n-3) fatty acid supplementation.22–24 The hemostatic abnormalities reflect changes in platelet function, bleeding time, and fibrinolysis. Platelet function may be altered by (n-3) fatty acids.19 Dietary (n-3) fatty acids are incorporated into platelet membranes. Activation of such platelets often leaves less arachidonic acid available for conversion to proaggregatory thromboxane A2 (TBA2). Activated platelets do not release eicosapentaenoic acid as readily, and eicosapentaenoic acid is a poor substrate for cyclooxygenase. In addition, eicosapentaenoic acid competitive-

ly inhibits the conversion of arachidonic acid to thromboxane A2. A net decrease in thromboxane A2, which is a potent vasoconstrictor and platelet aggregator, results. Although a diet consisting almost entirely of fish may cause thrombocytopenia, platelet count is usually unaffected by moderate doses of (n-3) fatty acids.25 Cutaneous bleeding time, which reflects the interaction between platelets and the vessel wall, is slightly prolonged after intake of (n-3) fatty acids26,27 in a dose-dependent fashion.28 Therefore, dietary (n-3) fatty acids modestly inhibit platelet reactivity. No clinically significant thrombocytopenia, no marked inhibition of platelet

Prostaglandins (2-series) Thromboxanes (2-series)

CYCLIC ENDOPEROXIDES

Prostaglandins (3-series) Thromboxanes (3-series)

CYCLIC ENDOPEROXIDES

PGI2 (prostacyclin)

PGI3

CYCLOOXYGENASE

ARACHIDONIC ACID

EICOSAPENTAENOIC ACID

5-LIPOXYGENASE

5-HPETE

LTA4

LTB4

LTC4

LTD4

(Series 4 leukotrienes)

5-HPEPE

LTA5

LTB5

LTC5

LTD5

(Series 5 leukotrienes)

Figure 3—The metabolism of the (n-6) fatty acid arachidonic acid and the (n-3) fatty acid eicosapentaenoic acid to

eicosanoids (LT = leukotriene, PGI2 = prostacyclin, PGI3 = prostaglandin I3, HPETE = hydroperoxyeicosatetraenoic acid, HPEPE = hydroperoxyeicosapentaenoic acid).

PLATELET FUNCTION ■ THROMBOXANE A2 ■ PLATELET COUNT

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function, and no bleeding have occurred in humans given moderate doses of fish oil.20 In one study, there were no differences in clotting time, prothrombin time, or partial thromboplastin time between treated dogs (given 1.8 mg of eicosapentaenoic acid daily for 6 weeks) and controls.29 In another study, after 4 weeks of diets supplemented with eicosapentaenoic acid, treated dogs showed a significant increase in bleeding time compared with control dogs.30 The dogs in the latter study were fed mackerel fish supplemented with menhaden oil (in an amount calculated to meet the daily requirements for protein and fat) as well as appropriate vitamin and mineral supplements. (This amount of marine oil was excessive and impractical as a diet.) After 60 days, mean bleeding times were twice as long for the dogs fed a marine fish diet than for control dogs.30 However, no deleterious short-term effects (e.g., no bleeding episodes) were noted clinically. Coagulability is probably not altered substantially, whereas fibrinolysis may be depressed by dietary (n-3) fatty acids.19 The agent responsible for fibrinolysis (the dissolution of fibrin) is plasmin, which is the activated form of plasminogen. Plasminogen can become activated by several mechanisms. Plasma also contains inhibitors to plasminogen activation. Plasma levels of the inhibitor of plasminogen activation increase in a dosedependent fashion following (n-3) fatty acid supplementation.28,31 The effects of (n-3) fatty acids on other indices of fibrinolysis are contradictory. Thus, fibrinolysis may be depressed by dietary (n-3) fatty acids.19 Depressed fibrinolysis has also been associated with hypertriglyceridemia.32 Triglyceride-rich lipoproteins transport a potent inhibitor of fibrinolysis. Hypertriglyceridemia and increased plasma concentration of fibrinogen are both important risk factors for ischemic heart disease in humans.33 Yet triglyceride and fibrinogen were significantly reduced when humans with ischemic heart disease were fed fish oil containing 18% eicosapentaenoic acid over a 7-year period.34 Therefore, the beneficial effects of (n-3) fatty acids in reducing levels of triglyceride and fibrinogen (and thus the pathologic processes leading to thrombotic occlusion) apparently outweigh the adverse effect of the depression of fibrinolysis by dietary (n-3) fatty acid supplementation.

Immune Reactivity Immune reactivity is generally reduced by (n-3) fatty acids.35–37 This effect may be beneficial in some conditions but could be detrimental in others. Animal and human studies have shown that production of eicosanoids and cytokines can be reduced by feeding diets high in long-chain (n-3) polyunsaturated fatty acids. For example, the synthesis of interleukin-1β, inter-

leukin-1α, and tumor necrosis factor are suppressed by dietary supplementation with long-chain (n-3) fatty acids.35 These cytokines are synthesized by monocytes and other cells in response to injury as well as to infectious, inflammatory, or immunologic challenges. Potential Clinical The suppression in synthesis Benefits of (n-3) Fatty of these substances may subseAcid Supplementation quently reduce the severity of certain autoimmune, inflammatory, or atherosclerotic dis- ■ Alleviate the pain eases. In humans, monocyte associated with hip and neutrophil chemotaxis is dysplasia8 also reduced in a dose-dependent fashion after (n-3) di- ■ Help control pruritus in dogs with atopy, etary supplementation.37 food allergy, or Meydani and coworkers demonstrated that feeding a fleabite allergy8,9–12 low-fat, low-cholesterol, mod- ■ Improve idiopathic erately high-fish diet for 24 seborrhea8 weeks to healthy, normolipidemic humans had significant ■ Suppress inflammation or effects on several parameters autoimmune diseases2 of immune and inflammatory 36 responses. Diets enriched ■ Improve with (n-3) fatty acids derived hypertrigylceridemia2 from fish significantly reduced ■ Decrease formation of delayed-type hypersensitivity thrombi2 skin response by 50% and the mitogenic response to con- ■ Inhibit tumorigenesis and influence tumor canavalin A by 34%; the percentage of T helper cells as growth7 well as production of interleukin-6 and interleukin-1β, tumor necrosis factor, and prostaglandin E2 were also reduced. The observed immunologic changes were probably not the result of decreased prostaglandin E2, which has been shown to suppress production of interleukin-1, tumor necrosis factor, and interleukin-2 as well as to suppress lymphocyte proliferation after stimulation with mitogens. More likely, the suppressive effects of diets enriched with (n-3) fatty acids resulted from the formation of eicosanoids derived from eicosapentaenoic acid (e.g., prostaglandin E3). As an alternative, a rise in lipid peroxide levels induced by (n-3) fatty acids could have contributed to the decrease in mitogenic and delayed-type hypersensitivity responses in skin tests.36 Whether the decreases observed in immune and inflammatory responses in these studies are sufficient to compromise the immune system is unknown. In healthy subjects or those with compromised immune status, reduction in the production of these cytokines

FIBRINOLYSIS ■ EICOSANOIDS ■ CYTOKINES ■ PROSTAGLANDIN E3

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or eicosanoids could compromise their normal basic biologic functions, thus possibly impairing host defenses.38 The decrease in the delayed-type hypersensitivity response, which is an in vivo measure of cell-mediated immunity, may have clinical significance because this test has been demonstrated to predict morbidity and mortality. Feeding fish oil to mice has been shown to decrease their natural resistance to infection with Salmonella typhimurium. Rats fed diets containing 9% menhaden oil had a shorter life span than did those fed corn oil or beef tallow. In rabbits given high doses of fish or safflower oil supplement (5 g/kg/day) for 7 days after birth, lung clearance of inhaled Staphylococcus aureus decreased by 50%. Fish-oil diets also augmented the non–histamine-mediated bronchoconstrictor response in pulmonary anaphylaxis.38 Therefore, cytokines and eicosanoids play a dual role as mediators of disease and mediators of defense.

Vitamin E Deficiency and Tissue Lipid Peroxidation Long-chain highly polyunsaturated (n-3) fatty acids in fish oil have the potential to undergo peroxidation and induce the formation of lipofuscin in tissue. Lipofuscin most likely develops through the formation of lipoperoxides from the oxidation of unsaturated fatty acids of membrane phospholipids. Excessive accumulation of lipofuscin may affect cell function and viability.39 A possible adverse effect of high levels of dietary (n-3) fatty acids is that their accumulation in tissue makes the tissue more vulnerable to lipid peroxidation, especially if peroxidation overwhelms the normal antioxidant mechanisms. Increased intake of (n-3) fatty acids without adequate antioxidant protection could result in increased free radicals, lipid-oxidative by-products, and lipofuscin formation. Whether this possibility is clinically relevant and whether it can be prevented by adding antioxidants to the diet are uncertain.19,25 Most fish-oil concentrates prepared for human consumption are enriched with antioxidants and are encapsulated; both measures help reduce the ex vivo oxidation of (n-3) fatty acids.25 Steatitis (yellow-fat disease) has been reported to occur in cats and swine consuming large quantities of fish or fish oil.40,41 This disease has been shown to be caused by vitamin E deficiency in cats.42 Ingestion of large amounts of polyunsaturated fatty acids without sufficient dietary antioxidant leads to peroxidation of depot fat with subsequent fat necrosis. Yellow discoloration of fat depots is caused by the accumulation of lipofuscin. Myocardial lipidosis has been reported to occur in young rats fed fish oil.43,44 Myocardial sensitivity to circu-

lating catecholamines has also been reported to occur in rats after ingestion of fish oil.45 A possible relationship between diet-induced alterations in cardiac phospholipid fatty acid composition and low isoproterenol tolerance may be related to the availability of arachidonic acid. Eicosanoid metabolites of arachidonic acid seem to have regulatory functions with regard to coronary tone. Interference with formation of these regulatory substances in overstimulated heart muscle may thus affect survival.45 On the other hand, an antiarrhythmic effect of (n-3) fatty acids has been reported to occur in animal models (rats and monkeys) following coronary artery ligation and reperfusion.19 Recent studies in primates, whose hearts are more similar to human hearts in the predominance of β-adrenergic receptors, indicated that diets enriched with either (n-6) or (n-3) fatty acids are beneficial in reducing the vulnerability to pharmacologically induced dysrhythmia in vitro or ischemic arrhythmia in vivo.46 Feeding fish oil, as opposed to vegetable oil, lowers the vitamin E content of mouse blood.47 Fish oil also has been shown to increase serum peroxide levels in rabbits.48 Dietary fish oil may adversely affect vitamin E concentrations in serum and tissue by overwhelming its antioxidant activity, thus leading to lipofuscin accumulation, which may subsequently impair function.49,50 The retina is particularly susceptible to age-related degeneration, lipid peroxidation, and lipofuscin accumulation.51 A high content of docosahexaenoic acid is normally present in the retina’s constituent phospholipids,52–54 and docosahexaenoic acid is important for normal visual acuity. Rhesus monkeys deprived of (n-3) fatty acids during prenatal and postnatal development showed depletion of (n-3) fatty acids from plasma lipids and a significant impairment of visual acuity. Visual loss was believed to be related to chemical changes in the retina and brain—specifically to reduced docosahexaenoic acid content in photoreceptor membranes and/or the occipital cortex and central visual system.53,54 The concentration of docosahexaenoic acid in the retina is increased further by feeding a diet rich in longchain (n-3) fatty acids. A high content of docosahexaenoic acid can have important biological disadvantages—in particular, vulnerability to lipid peroxidation. When rats are fed a diet high in polyunsaturated fatty acids and deficient in vitamin E, lipid peroxidation increases and lipofuscin accumulates in the retina.51 Docosahexaenoic acid in the diet is essential for normal visual acuity; but because of its high docosahexaenoic acid content, the retina is particularly sensitive to lipid peroxidation. Therefore, the levels of vitamin E in the diet enriched with (n-3) fatty acids must be adequate to prevent lipid peroxidation in tissue.

STEATITIS ■ MYOCARDIAL LIPIDOSIS ■ RETINA ■ VISUAL ACTIVITY ■ LIPOFUSCIN

The Compendium August 1996

In human studies, dietary fish oils have had no consistent effects on antioxidant levels (including vitamin E) in plasma or various types of cells.19 Although currently recommended levels of vitamin E in the diet may be adequate to prevent deficiency disease, they may be inadequate to prevent oxidation of lipids and free radical damage or to promote optimal health. Women given polyunsaturated fatty acid (fish oil) supplements (2.4 g/day) for 3 months had increased plasma lipid peroxide levels despite no significant change in plasma vitamin E levels.55 Research data for humans suggest that considerably more vitamin E than is consumed in the average diet is necessary to prevent damage by free radicals.56,57 Inadequate levels of vitamin E may be added to diets on the basis of existing formulas, thus resulting in higher lipid peroxide production and decreased plasma tocopherol concentrations.58 Could the fall in vitamin E levels have adverse effects? Epidemiologic studies provide data indicating that humans with higher blood levels of vitamin E have a reduced risk of developing cancer.59–62 Vitamin E supplementation improves immune responsiveness in healthy elderly individuals.63 This effect appears to be mediated by a decrease in prostaglandin E2 and/or a decrease in lipid-peroxidation products. To prevent lipid peroxidation, vitamin E levels will therefore need to be closely monitored as (n-3) fatty acid consumption increases.

Hyperglycemia Fish oil fed to humans with diabetes mellitus has led to conflicting data about its effects on insulin release from the pancreas, peripheral insulin resistance, and glucose tolerance. Some studies have shown that addition of (n-3) fatty acids to the diet of humans with type II diabetes may increase blood glucose levels without a concomitant increase in insulin levels.64–66 The rate of glucose disappearance, which reflects the peripheral insulin sensitivity, also tends to decrease when fish oil is eaten.66 Other researchers have reported that dietary supplementation of (n-3) polyunsaturated fatty acids improves insulin sensitivity in humans with non–insulin-dependent diabetes.67 The reasons for the contradictory findings in blood glucose concentration and insulin sensitivity in human patients with diabetes are poorly understood.19 A potential linkage between increased intake of (n-3) fatty acids and inhibition of insulin release could occur by altering lipoxygenase products.68 The long-term effects of feeding (n-3) polyunsaturated fatty acids to normal dogs and cats on glycemic control have not been studied. In normoglycemic elderly humans, fish consumption was inversely related to the risk of future glucose intolerance.69

Small Animal

Competition with Other Fatty Acids Because the (n-3) fatty acids are much more effective in inhibiting (n-6) fatty acid metabolism than vice versa, there is a substantial risk that high intakes of (n-3) fatty acids could lead to impairment of linoleic acid metabolism and a deficit of its (n-6) fatty-acid derivatives.4 Results from three trials in which humans were given high doses of fish oil showed a decrease in the plasma levels of the (n-6) fatty acids dihomo-γ-linolenic acid and arachidonic acid.70–72 Could the fall in (n-6) fatty acids have adverse effects? Overall, (n-6) fatty acids are considerably more important than (n-3) fatty acids. Linoleic acid is considered essential to prevent signs of deficiency in almost every system of the body.73,74 In cats, arachidonic acid is considered essential because cats cannot make adequate amounts of arachidonic acid from linoleic acid.3 Fishoil intake might therefore produce a detrimental reduction in arachidonic acid.4 The (n-3) fatty acids have only recently been shown to have specific roles within the retina and nervous system.52 Dihomo-γ-linolenic acid is an (n-6) fatty acid with a wide range of cardiovascular and antiinflammatory actions.4 It is present in most tissues at levels two to six times higher than those of eicosapentaenoic acid. 4 Compared with arachidonic acid, dihomo-γ-linolenic acid is more affected by fish-oil intake, as evidenced by a mean fall in plasma dihomo-γ-linolenic acid of 50% after fish oil consumption in three human studies.70–72 The (n-3) fatty acids inhibit formation of dihomo-γlinolenic acid apparently by reducing the conversion of linoleic acid to γ-linolenic acid. A diet that is rich in (n3) fatty acids does not reduce dihomo-γ-linolenic acid levels when γ-linolenic acid is provided in the diet because the elongation step in conversion of γ-linolenic acid to dihomo-γ-linolenic acid seems resistant to inhibition by (n-3) fatty acids. Dihomo-γ-linolenic acid gives rise to at least two metabolites that have desirable actions: prostaglandin E1 and a 15-hydroxyl derivative (15-hydroxydihomo-γ-linolenic acid).75 Prostaglandin E1 lowers cholesterol levels and is also a powerful antiinflammatory agent that has been shown to inhibit inflammation in many different models.4 The other metabolite, 15-hydroxydihomo-γ-linolenic acid, inhibits the activity of both 5- and 12-lipoxygenase, thus reducing the production of proinflammatory eicosanoids from arachidonic acid.75,76 The 5- and 12lipoxygenases are enzymes that catalyze the generation of two proinflammatory mediators (12-hydroxyeicosatetraenoic acid [12-HETE] and leukotriene B4 [LTB4]) from arachidonic acid. In light of these positive effects of dihomo-γ-linolenic acid, it must be questioned whether raising concentra-

GLUCOSE DISAPPEARANCE ■ INSULIN SENSITIVITY ■ PROSTAGLANDIN E1

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tions of eicosapentaenoic acid at the expense of dihomo-γ-linolenic acid is a risk-free strategy.4 The optimum strategy for using fatty acids to prevent and treat cardiovascular and inflammatory diseases may be to raise the levels of dihomo-γ-linolenic acid (which is an [n-6] fatty acid) by providing dietary γ-linolenic acid while simultaneously raising levels of eicosapentaenoic acid (an [n-3] fatty acid). This approach has already been successful in the treatment of rheumatoid arthritis in humans.4,77 Otherwise, the antiinflammatory effects that may accrue from the displacement of arachidonic acid from phospholipids by eicosapentaenoic acid could be mitigated by an associated reduction in dihomo-γ-linolenic acid.72

Atherosclerosis Whether (n-3) fatty acid supplementation is effective in the prevention or treatment of atherosclerosis in humans is controversial.4 Although this disorder is not a major concern in small animal medicine, it is interesting to note the potential adverse effects of (n-3) fatty acid consumption on risk factors for coronary heart disease (namely, low-density lipoprotein [LDL] cholesterol). In several studies, fish-oil consumption significantly increased LDL cholesterol—even when fed in very low, clinically practical doses.78,79 Fish oil has also adversely affected serum lipids to yield an atherogenic lipid profile in hypertensive men.80 As mentioned, eicosapentaenoic acid and docosahexaenoic acid (which are [n-3] fatty acids) are more subject to oxidation than is arachidonic acid (an [n-6] fatty acid). Oxidation of the fatty acids may increase the atherogenicity of the LDL particles containing them. In humans, there is growing evidence that lipid peroxidation, especially oxidation of LDL cholesterol, may play a pivotal role in atherogenesis.25 Whether dietary (n-3) fatty acids could lead to a clinically relevant increase in oxidation of LDL in vivo or whether this is prevented by added antioxidants is unknown.19 Epidemiologic and experimental data show no increase in atherosclerosis induced by (n-3) fatty acids.21 Tolerance In human clinical trials, dietary supplementation with (n-3) polyunsaturated fatty acids has been well tolerated. Over a 5-year period, one research group reported that mild gastrointestinal adverse effects had occurred but often subsided during continued intake of (n-3) fatty acids.25 No bleeding episodes were reported, and no one withdrew from the trials because of adverse effects. In a study of dogs, reported side effects of (n-3) fatty acid supplementation included lethargy, pruritus, vom-

iting, diarrhea, and urticaria (4 of 45 dogs).81 No bleeding episodes were reported. Two dogs were withdrawn from the trial because of adverse effects.

SUMMARY Dietary supplementation with (n-3) fatty acids seems to be well tolerated and without serious adverse effects in humans. However, caution should always be exercised in extrapolating data from studies of humans or other species to dogs or cats. Nevertheless, the major safety issues of long-term dietary intake of (n-3) fatty acids appear to be increased lipid peroxidation, risk of bleeding, and immunoincompetence. At present, it seems important to recommend a high dietary intake of vitamin E to prevent the production of harmful oxidation products and to choose dietary (n-3) fatty acid supplements that contain added antioxidants. The risk of bleeding seems minimal. There have been no reports of bleeding during human clinical trials of fish-oil supplementation.21 Whether (n-3) fatty acids can suppress the immune system below its normal level of competence is unknown. Competition between fatty acids for metabolic pathways should also be considered. Research is needed to determine whether increased levels of dihomo-γlinolenic acid and eicosapentaenoic acid in the diet are necessary to achieve optimum health for dogs and cats, as it is in the successful treatment of rheumatoid arthritis in humans.4,77 Long-term studies examining the beneficial effects of dietary (n-3) fatty acid supplementation in small animal patients provide an excellent opportunity to study the possible toxic or unfavorable effects. Few studies have focused on the adverse effects, tolerability, and safety issues of (n-3) fatty acid administration to dogs or cats. Such safety studies are indicated before widespread or unconditional recommendations can be made regarding long-term supplementation with (n-3) fatty acids or alteration of the ratio of (n-3) to (n-6) fatty acids in the diet. About the Author Dr. Hall is affiliated with the College of Veterinary Medicine, Oregon State University, Corvallis, Oregon, and is a Diplomate of the American College of Veterinary Internal Medicine (Internal Medicine).

REFERENCES 1. Dyerberg J: n-3 Fatty acids: Epidemiological background and general introduction, in De Caterina R, Kristensen SD, Schmidt EB (eds): Fish Oil and Vascular Disease. Berlin, Springer-Verlag, 1992, pp 3–8.

LETHARGY ■ PRURITUS ■ VOMITING ■ DIARRHEA ■ URTICARIA

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