Potential Adverse Effects of Long-term Consumption of Fatty Acids

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Vol.18, No. 8 August 1996

Potential AdverseEffects of Long-TermConsumption of (n-3)

Fatty Acids*

Oregon State University

Jean A. Hall, DVM, PhD

The potential benefits of dietary supplementation with (n-3) (also called-3) fatty acids have aroused great interest. As a result, various petfoods and fatty acid supplements rich in (n-3) fatty acids are currentlymarketed for administration to dogs and cats. However, long-term studies ofthe effects of dietary supplementation with (n-3) fatty acids in these species arelacking. Potential toxic or adverse effects of long-term (n-3) fatty acid con-sumption should not be ignored but should be investigated in conjunction

with ongoing research to determine whether diseased dogs or cats will benefitfrom the use of these agents.

POLYUNSATURATED FATTY ACIDSOverview

Fatty acids are classified as saturated, monounsaturated, or polyunsaturatedon the basis of the number of double bonds in the fatty acids carbon chain.Each class of fatty acids has different properties and unique biologic character-istics.1,2

Polyunsaturated fatty acids are named according to the position of the firstdouble bondcounting from the methyl end of the molecule (Figure 1). Thetwo 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

Continuing Education Article

V

FOCAL POINT

KEY FACTS

s The risk of bleeding after

prolonged intake of (n-3) fatty

acids seems to be very low.

s 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.

s 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.

s Whether the observed decreases

in immune and inflammatory

responses are sufficient to

compromise normal hostdefenses is unknown.

5The long-term effects of (n-3)fatty acid supplementation for

companion animals have not

been investigated.

*Editors Note:This article, which was derived in part from a presentation at the Thir-teenth ACVIM Veterinary Medical Forum, is presented to give the reader an overviewof potential adverse effects of (n-3) fatty acid supplementation. Although these productsappear to be very safe as currently used, their long-term effects in companion animalshave not been studied. Most of the information regarding adverse effects is taken fromstudies of humans. A second article describing the benefits of fatty acid supplementationin small animals will be presented in an upcoming issue of Compendium.As with allnew therapies, practitioners must weigh the costs and benefits before making recom-mendations.


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(n-6) series (which have thefirst double bond located atthe sixth carbon atom).

Both linoleic acid and -linolenic acid, which are

the precursors of the (n-6)and (n-3) series, respective-ly, are essential fatty acidsbecause mammals cannotsynthesize them from otherseries of fatty acids. Mam-mals lack the enzymes tointroduce double bonds atcarbon atoms before theninth carbon atom in thefatty acid chain (countingfrom the methyl end).

Therefore, these essentialfatty acids must be suppliedin the diet. Subsequent de-saturation and elongationproceed only toward thecarboxyl terminus of the fatty acid.

In general, fatty acids from both series can be elon-gated and desaturated. Cats, however, have reduced 6desaturase and therefore cannot adequately convertlinoleic acid to arachidonic acid. Thus, arachidonicacid and linoleic acid must be supplied by the cat sdiet.3

The elongation (increase in the number of carbonatoms) and desaturation (increase in the number ofdouble bonds) of linoleic acid and -linolenic acid arecatalyzed by the same enzymes (Figure 2). However, in-terconversion between (n-3) fatty acids and (n-6) fattyacids is impossible because elongation and desaturationoccur only toward the carboxyl terminus of the fattyacid.

Arachidonic acid (which is derived from the [n-6]fatty acid linoleic acid) and eicosapentaenoic acid(which is derived from the [n-3] fatty acid -linolenicacid) are both fundamental components of cytoplasmic

membranes. Further metabolism of these fatty acidsleads to the generation of eicosanoids (Figure 3).Prostaglandins, thromboxanes, and leukotrienes are allderived from the metabolism of (n-3) and (n-6) fattyacids through reactions involving cyclooxygenase andlipoxygenase enzymes.

Eicosanoids are important mediators of cellular reac-tions. The eicosanoids derived from arachidonic acidand eicosapentaenoic acid have different biologic ef-fects. For example, the eicosanoids that are derivedfrom eicosapentaenoic acid are in general much less po-tent inducers of inflammation than are the eicosanoids

derived from arachidonicacid.

Although no conversionbetween (n-3) and (n-6) se-ries of fatty acids takes

place, inhibition and com-petition between fatty acidsof different series have beendemonstrated.46 For exam-ple, the metabolism of-linolenic acid is inhibitedby members of the linoleic-acid family: arachidonicacid, -linolenic acid, andlinoleic acid. The competi-tive equilibrium betweenlinoleate and linolenate can

be displaced in either direc-tion, and the fatty acid fa-vored in the competitiondepends on the relative lev-els of those fatty acids in

the diet.6 An excess of (n-6) fatty acids reduces themetabolism of-linolenic acid, thus possibly leading toa deficit of its metabolites, including eicosapentaenoicacid. However, the (n-3) fatty acids are much more ef-fective in inhibiting (n-6) fatty acid metabolism thanvice versa.4

SourcesVarious diets and nutritional supplements are cur-rently marketed as sources of (n-3) fatty acids for com-panion animals. The fatty acid ratios of commercialdog foods vary widely, depending on the source of fat.Diets containing safflower oil or corn oil are likely to behigh in (n-6) fatty acids and to have a ratio of (n-6) to(n-3) greater than 30:1. Also, various (n-3) fatty acidsupplements for human use are available over thecounter.

(N-3) FATTY ACID SUPPLEMENTATION

Potential Clinical BenefitsDietary supplementation with (n-3) fatty acids mayproduce desirable clinical effects in dogs or cats withvarious diseases.2,79 In addition, extrapolation fromstudies of animal models and human trials indicatesthat these fatty acids have the potential to yield variousclinical benefits (see the box). Some of the potentialbenefits for cancer patients relate to the ability of (n-3)fatty acids to decrease production of certain cytokinesthat mediate cancer cachexia.

Because of their ability to modify eicosanoid produc-tion, (n-3) fatty acids have the potential to alter func-

Small Animal The Compendium August 1996

A R A C H I D O N I C A C I D s E I C O S A P E N T A E N O I C A C I D s F A T T Y A C I D R A T I O S

Linoleic acid 18:2 (n-6)

COOH

COOH

CH3

CH3

-Linolenic acid 18:3 (n-3)

Figure 1Polyunsaturated fatty acids of the (n-6) series(linoleic acid 18:2 [n-6]) and of the (n-3) series (-linolenic

acid 18:3 [n-3]). The number of carbon atoms is listed be-fore the colon and the number of double bonds after thecolon.


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tion or disease processes in many different body sys-

tems (e.g., the gastrointestinal and renal systems) thatare influenced by prostaglandins.1317 Whether dietarysupplementation with (n-3) fatty acids will be benefi-cial in the treatment of the disease processes discussedremains to be seen.

Potential Adverse EffectsMany of the studies cited below have been conducted

with research animals or with human patients. Thedosages used, the duration of the feeding trials, andthus the biologic responses often vary between studies.For example, the response to fish consumption may be

compared with the responseto fish-oil consumption orto a specific dose of (n-3)fatty acids. In addition,there are inherent problems

in extrapolating from otherspecies to dogs and cats.The effects of dietary

supplementation with (n-3)fatty acids for dogs and catshave not been well studied.Experimental data on thecorrect dosage of (n-3) fattyacids or the best ratio of (n-6) to (n-3) fatty acids in thediet for maximizing benefitsand minimizing side effects

are few. Nevertheless, the fol-lowing safety issues shouldbe considered before long-term dietary supplementa-tion with (n-3) fatty acids isrecommended.

Contaminationof Sources

Fish oil, which is a majordietary source of (n-3) fattyacids, may contain heavy

metals and organic chemi-cals that were concentratedin the lipids of fish caughtin waters contaminated withindustrial by-products (e.g.,dioxin and dibenzofurans).18

These findings do not war-rant restriction of the con-sumption of fish oil butshould serve as a reminderof potential food contami-

nation by these toxic substances. Heavy metals and pes-

ticides may be removed during the processing of fish-oil concentrates.19 Veterinarians prescribing (n-3) fattyacid supplements should ask commercial suppliers ifthe products are free of contaminants. Most manufac-turers carefully screen their oils to ensure that they donot contain unwanted substances.

Hemostatic AbnormalitiesMany studies have addressed the concern about an

increased risk of bleeding after prolonged intake of (n-3) fatty acids,20 but the risk seems to be very low.21 Pro-thrombin time, activated partial thromboplastin time,

The Compendium August 1996 Small Animal

D I O X I N s D I B E N Z O F U R A N S s H E A V Y M E T A L S s P E S T I C I D E S

Figure 2Fatty acid biosynthesis: the elongation and desaturation of the (n-6) fatty acidlinoleic acid and the (n-3) fatty acid -linolenic acid.

Linoleic acid

18:2 (n-6)

-Linolenic acid

18:3 (n-6)

Dihomo--linolenic acid

20:3 (n-6)

Arachidonic acid20:4 (n-6)

22:4 (n-6)

22:5 (n-6)

-Linolenic acid

18:3 (n-3)

Stearidonic acid18:4 (n-3)

Eicosatetraenoic acid

20:4 (n-3)

Eicosapentaenoic acid20:5 (n-3)

22:5 (n-3)

Docosahexaenoic acid22:6 (n-3)

(n-6) Series (n-3) Series

6 Desaturase(desaturation)

Elongase(elongation)


Elongase(elongation)



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and plasma levels of thrombin-antithrombin complexesare usually unaltered by (n-3) fatty acid supplementa-tion.2224 The hemostatic abnormalities reflect changesin 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 plateletmembranes. Activation of such platelets often leavesless arachidonic acid available for conversion to proag-gregatory thromboxane A2 (TBA2). Activated plateletsdo not release eicosapentaenoic acid as readily, andeicosapentaenoic acid is a poor substrate for cyclooxy-genase. In addition, eicosapentaenoic acid competitive-

ly inhibits the conversion of arachidonic acid to throm-boxane A2. A net decrease in thromboxane A2, which isa potent vasoconstrictor and platelet aggregator, results.

Although a diet consisting almost entirely of fish maycause thrombocytopenia, platelet count is usually unaf-

fected by moderate doses of (n-3) fatty acids.

25

Cuta-neous bleeding time, which reflects the interaction be-tween platelets and the vessel wall, is slightly prolongedafter intake of (n-3) fatty acids26,27 in a dose-dependentfashion.28 Therefore, dietary (n-3) fatty acids modestlyinhibit platelet reactivity. No clinically significantthrombocytopenia, no marked inhibition of platelet


P L A T E L E T F U N C T I O N s T H R O M B O X A N E A 2 s P L A T E L E T C O U N T

Figure 3The metabolism of the (n-6) fatty acid arachidonic acid and the (n-3) fatty acid eicosapentaenoic acid toeicosanoids (LT= leukotriene, PGI2 = prostacyclin, PGI3 = prostaglandin I3, HPETE = hydroperoxyeicosatetraenoic acid,HPEPE= hydroperoxyeicosapentaenoic acid).

CYCLIC ENDOPEROXIDES

Prostaglandins(2-series)

Thromboxanes(2-series)

PGI2 (prostacyclin)

CYCLIC ENDOPEROXIDES

Prostaglandins(3-series)

Thromboxanes(3-series)

PGI3

ARACHIDONICACID

EICOSAPENTAENOICACID

CYCLOOXYGENASE

5-LIPOXYGENASE

5-HPETE LTA4 LTB4

LTC4 LTD4

(Series 4 leukotrienes)

5-HPEPE LTA5 LTB5

LTC5 LTD5

(Series 5 leukotrienes)


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function, and no bleeding have occurred in humansgiven moderate doses of fish oil.20

In one study, there were no differences in clottingtime, prothrombin time, or partial thromboplastintime between treated dogs (given 1.8 mg of eicosapen-

taenoic acid daily for 6 weeks) and controls.

29

In anoth-er study, after 4 weeks of diets supplemented witheicosapentaenoic acid, treated dogs showed a significantincrease in bleeding time compared with control dogs.30

The dogs in the latter study were fed mackerel fish sup-plemented with menhaden oil (in an amount calculatedto meet the daily requirements for protein and fat) as

well as appropriate vitamin and mineral supplements.(This amount of marine oil was excessive and impracti-cal as a diet.) After 60 days, mean bleeding times weretwice as long for the dogs fed a marine fish diet thanfor 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 (thedissolution of fibrin) is plasmin, which is the activatedform of plasminogen. Plasminogen can become activat-ed by several mechanisms. Plasma also contains in-hibitors to plasminogen activation. Plasma levels of theinhibitor of plasminogen activation increase in a dose-dependent fashion following (n-3) fatty acid supple-mentation.28,31 The effects of (n-3) fatty acids on otherindices of fibrinolysis are contradictory. Thus, fibrinol-

ysis may be depressed by dietary (n-3) fatty acids.

19

Depressed fibrinolysis has also been associated withhypertriglyceridemia.32 Triglyceride-rich lipoproteinstransport a potent inhibitor of fibrinolysis. Hyper-triglyceridemia and increased plasma concentration offibrinogen are both important risk factors for ischemicheart disease in humans.33 Yet triglyceride and fibrino-gen were significantly reduced when humans with isch-emic 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 lev-els of triglyceride and fibrinogen (and thus the patho-

logic processes leading to thrombotic occlusion) appar-ently outweigh the adverse effect of the depression offibrinolysis by dietary (n-3) fatty acid supplementation.

Immune ReactivityImmune reactivity is generally reduced by (n-3) fatty

acids.3537 This effect may be beneficial in some condi-tions but could be detrimental in others. Animal andhuman studies have shown that production of eico-sanoids and cytokines can be reduced by feeding dietshigh in long-chain (n-3) polyunsaturated fatty acids.For example, the synthesis of interleukin-1, inter-

leukin-1, and tumor necrosis factor are suppressed bydietary supplementation with long-chain (n-3) fattyacids.35 These cytokines are synthesized by monocytesand other cells in response to injury as well as to infec-tious, inflammatory, or im-

munologic challenges.The suppression in synthesisof these substances may subse-quently reduce the severity ofcertain autoimmune, inflam-matory, or atherosclerotic dis-eases. In humans, monocyteand neutrophil chemotaxis isalso reduced in a dose-depen-dent fashion after (n-3) di-etary supplementation.37

Meydani and coworkers

demonstrated that feeding alow-fat, low-cholesterol, mod-erately high-fish diet for 24

weeks to healthy, normolipi-demic humans had significanteffects on several parametersof immune and inflammatoryresponses.36 Diets enriched

with (n-3) fatty acids derivedfrom fish significantly reduceddelayed-type hypersensitivityskin response by 50% and the

mitogenic response to con-canavalin A by 34%; the per-centage of T helper cells as

well as production of inter-leukin-6 and interleukin-1,tumor necrosis factor, and prostaglandin E2 were alsoreduced.

The observed immunologic changes were probablynot the result of decreased prostaglandin E2, which hasbeen shown to suppress production of interleukin-1,tumor necrosis factor, and interleukin-2 as well as tosuppress lymphocyte proliferation after stimulation

with mitogens. More likely, the suppressive effects ofdiets enriched with (n-3) fatty acids resulted from theformation of eicosanoids derived from eicosapentaenoicacid (e.g., prostaglandin E3). As an alternative, a rise inlipid peroxide levels induced by (n-3) fatty acids couldhave contributed to the decrease in mitogenic and de-layed-type hypersensitivity responses in skin tests.36

Whether the decreases observed in immune and in-flammatory responses in these studies are sufficient tocompromise the immune system is unknown. Inhealthy subjects or those with compromised immunestatus, reduction in the production of these cytokines


F I B R I N O L Y S I S s E I C O S A N O I D S s C Y T O K I N E S s P R O S T A G L A N D I N E 3

Potential ClinicalBenefits of (n-3) Fatty

Acid Supplementation

s Alleviate the pain

associated with hip

dysplasia8

s Help control pruritus

in dogs with atopy,

food allergy, or

fleabite allergy8,912

s Improve idiopathic

seborrhea8

s Suppress

inflammation or

autoimmune diseases2

s Improve

hypertrigylceridemia2

s Decrease formation of

thrombi2

s Inhibit tumorigenesis

and influence tumor

growth7


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or eicosanoids could compromise their normal basicbiologic functions, thus possibly impairing host defens-es.38 The decrease in the delayed-type hypersensitivityresponse, which is an in vivo measure of cell-mediatedimmunity, may have clinical significance because this

test has been demonstrated to predict morbidity andmortality.Feeding fish oil to mice has been shown to decrease

their natural resistance to infection with Salmonellatyphimurium. Rats fed diets containing 9% menhadenoil had a shorter life span than did those fed corn oil orbeef tallow. In rabbits given high doses of fish or saf-flower oil supplement (5 g/kg/day) for 7 days afterbirth, lung clearance of inhaled Staphylococcus aureusdecreased by 50%. Fish-oil diets also augmented thenonhistamine-mediated bronchoconstrictor responsein pulmonary anaphylaxis.38 Therefore, cytokines and

eicosanoids play a dual role as mediators of disease andmediators of defense.

Vitamin E Deficiency andTissue Lipid Peroxidation

Long-chain highly polyunsaturated (n-3) fatty acidsin fish oil have the potential to undergo peroxidationand induce the formation of lipofuscin in tissue. Lipo-fuscin most likely develops through the formation oflipoperoxides from the oxidation of unsaturated fattyacids of membrane phospholipids. Excessive accumula-tion of lipofuscin may affect cell function and viabili-

ty.

39

A possible adverse effect of high levels of dietary(n-3) fatty acids is that their accumulation in tissuemakes the tissue more vulnerable to lipid peroxidation,especially if peroxidation overwhelms the normal an-tioxidant mechanisms.

Increased intake of (n-3) fatty acids without adequateantioxidant protection could result in increased freeradicals, lipid-oxidative by-products, and lipofuscin for-mation. Whether this possibility is clinically relevantand whether it can be prevented by adding antioxidantsto the diet are uncertain.19,25 Most fish-oil concentratesprepared for human consumption are enriched with

antioxidants and are encapsulated; both measures helpreduce the ex vivo oxidation of (n-3) fatty acids.25

Steatitis (yellow-fat disease) has been reported to oc-cur in cats and swine consuming large quantities of fishor fish oil.40,41 This disease has been shown to be causedby vitamin E deficiency in cats.42 Ingestion of largeamounts of polyunsaturated fatty acids without suffi-cient dietary antioxidant leads to peroxidation of depotfat with subsequent fat necrosis. Yellow discoloration offat depots is caused by the accumulation of lipofuscin.

Myocardial lipidosis has been reported to occur inyoung rats fed fish oil.43,44 Myocardial sensitivity to circu-

lating catecholamines has also been reported to occur inrats after ingestion of fish oil.45 A possible relationshipbetween diet-induced alterations in cardiac phospholipidfatty acid composition and low isoproterenol tolerancemay be related to the availability of arachidonic acid.

Eicosanoid metabolites of arachidonic acid seem tohave regulatory functions with regard to coronary tone.Interference with formation of these regulatory sub-stances in overstimulated heart muscle may thus affectsurvival.45 On the other hand, an antiarrhythmic effectof (n-3) fatty acids has been reported to occur in ani-mal models (rats and monkeys) following coronaryartery ligation and reperfusion.19 Recent studies in pri-mates, whose hearts are more similar to human heartsin the predominance of-adrenergic receptors, indicat-ed that diets enriched with either (n-6) or (n-3) fattyacids are beneficial in reducing the vulnerability to

pharmacologically induced dysrhythmia in vitro orischemic arrhythmia in vivo.46

Feeding fish oil, as opposed to vegetable oil, lowersthe vitamin E content of mouse blood.47 Fish oil alsohas been shown to increase serum peroxide levels inrabbits.48 Dietary fish oil may adversely affect vitamin Econcentrations in serum and tissue by overwhelming itsantioxidant activity, thus leading to lipofuscin accumu-lation, which may subsequently impair function.49,50

The retina is particularly susceptible to age-relateddegeneration, lipid peroxidation, and lipofuscin accu-mulation.51 A high content of docosahexaenoic acid is

normally present in the retinas constituent phospho-lipids,5254 and docosahexaenoic acid is important fornormal visual acuity. Rhesus monkeys deprived of (n-3)fatty acids during prenatal and postnatal developmentshowed depletion of (n-3) fatty acids from plasmalipids and a significant impairment of visual acuity. Vi-sual loss was believed to be related to chemical changesin the retina and brainspecifically to reduced docosa-hexaenoic acid content in photoreceptor membranesand/or the occipital cortex and central visual system.53,54

The concentration of docosahexaenoic acid in theretina is increased further by feeding a diet rich in long-

chain (n-3) fatty acids. A high content of docosahexa-enoic acid can have important biological disadvan-tagesin particular, vulnerability to lipid peroxidation.

When rats are fed a diet high in polyunsaturated fattyacids and deficient in vitamin E, lipid peroxidation in-creases and lipofuscin accumulates in the retina.51

Docosahexaenoic acid in the diet is essential for nor-mal visual acuity; but because of its high docosahexa-enoic acid content, the retina is particularly sensitive tolipid peroxidation. Therefore, the levels of vitamin E inthe diet enriched with (n-3) fatty acids must be ade-quate to prevent lipid peroxidation in tissue.


S T E A T I T I S s M Y O C A R D I A L L I P I D O S I S s R E T I N A s V I S U A L A C T I V I T Y s L I P O F U S C I N


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In human studies, dietary fish oils have had no con-sistent effects on antioxidant levels (including vitaminE) in plasma or various types of cells.19 Although cur-rently recommended levels of vitamin E in the diet maybe adequate to prevent deficiency disease, they may be

inadequate to prevent oxidation of lipids and free radi-cal damage or to promote optimal health.Women given polyunsaturated fatty acid (fish oil)

supplements (2.4 g/day) for 3 months had increasedplasma lipid peroxide levels despite no significant changein plasma vitamin E levels.55 Research data for humanssuggest that considerably more vitamin E than is con-sumed in the average diet is necessary to prevent dam-age by free radicals.56,57 Inadequate levels of vitamin Emay be added to diets on the basis of existing formulas,thus resulting in higher lipid peroxide production anddecreased plasma tocopherol concentrations.58

Could the fall in vitamin E levels have adverse effects?Epidemiologic studies provide data indicating that hu-mans with higher blood levels of vitamin E have a re-duced risk of developing cancer.5962 Vitamin E supple-mentation improves immune responsiveness in healthyelderly individuals.63 This effect appears to be mediatedby a decrease in prostaglandin E2 and/or a decrease inlipid-peroxidation products. To prevent lipid peroxida-tion, vitamin E levels will therefore need to be closelymonitored as (n-3) fatty acid consumption increases.

Hyperglycemia

Fish oil fed to humans with diabetes mellitus has ledto conflicting data about its effects on insulin releasefrom the pancreas, peripheral insulin resistance, andglucose tolerance. Some studies have shown that addi-tion of (n-3) fatty acids to the diet of humans with typeII diabetes may increase blood glucose levels without aconcomitant increase in insulin levels.6466 The rate ofglucose disappearance, which reflects the peripheral in-sulin sensitivity, also tends to decrease when fish oil iseaten.66 Other researchers have reported that dietarysupplementation of (n-3) polyunsaturated fatty acidsimproves insulin sensitivity in humans with nonin-

sulin-dependent diabetes.67

The reasons for the contradictory findings in bloodglucose concentration and insulin sensitivity in humanpatients with diabetes are poorly understood.19 A po-tential linkage between increased intake of (n-3) fattyacids and inhibition of insulin release could occur byaltering lipoxygenase products.68

The long-term effects of feeding (n-3) polyunsaturat-ed fatty acids to normal dogs and cats on glycemic con-trol have not been studied. In normoglycemic elderlyhumans, fish consumption was inversely related to therisk of future glucose intolerance.69

Competition with Other Fatty AcidsBecause the (n-3) fatty acids are much more effective

in inhibiting (n-6) fatty acid metabolism than vice ver-sa, 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 deriva-tives.4 Results from three trials in which humans weregiven high doses of fish oil showed a decrease in theplasma levels of the (n-6) fatty acids dihomo--linolenicacid and arachidonic acid.7072

Could the fall in (n-6) fatty acids have adverse ef-fects? Overall, (n-6) fatty acids are considerably moreimportant than (n-3) fatty acids. Linoleic acid is con-sidered essential to prevent signs of deficiency in almostevery system of the body.73,74 In cats, arachidonic acid isconsidered essential because cats cannot make adequateamounts of arachidonic acid from linoleic acid.3 Fish-

oil intake might therefore produce a detrimental reduc-tion in arachidonic acid.4 The (n-3) fatty acids haveonly recently been shown to have specific roles withinthe retina and nervous system.52

Dihomo--linolenic acid is an (n-6) fatty acid with awide range of cardiovascular and antiinflammatory ac-tions.4 It is present in most tissues at levels two to sixtimes higher than those of eicosapentaenoic acid.4

Compared with arachidonic acid, dihomo--linolenicacid is more affected by fish-oil intake, as evidenced bya mean fall in plasma dihomo--linolenic acid of 50%after fish oil consumption in three human studies.7072

The (n-3) fatty acids inhibit formation of dihomo--linolenic acid apparently by reducing the conversion oflinoleic acid to -linolenic acid. A diet that is rich in (n-3) fatty acids does not reduce dihomo--linolenic acidlevels when -linolenic acid is provided in the diet be-cause the elongation step in conversion of -linolenicacid to dihomo--linolenic acid seems resistant to inhi-bition by (n-3) fatty acids. Dihomo--linolenic acidgives rise to at least two metabolites that have desirableactions: prostaglandin E1 and a 15-hydroxyl derivative(15-hydroxydihomo--linolenic acid).75

Prostaglandin E1 lowers cholesterol levels and is also a

powerful antiinflammatory agent that has been shownto inhibit inflammation in many different models.4 Theother metabolite, 15-hydroxydihomo--linolenic acid,inhibits the activity of both 5- and 12-lipoxygenase,thus reducing the production of proinflammatoryeicosanoids from arachidonic acid.75,76 The 5- and 12-lipoxygenases are enzymes that catalyze the generationof two proinflammatory mediators (12-hydroxyeicosa-tetraenoic acid [12-HETE] and leukotriene B4 [LTB4])from arachidonic acid.

In light of these positive effects of dihomo--linolenicacid, it must be questioned whether raising concentra-


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tions of eicosapentaenoic acid at the expense of diho-mo--linolenic acid is a risk-free strategy.4 The opti-mum strategy for using fatty acids to prevent and treatcardiovascular and inflammatory diseases may be toraise the levels of dihomo--linolenic acid (which is an

[n-6] fatty acid) by providing dietary-linolenic acidwhile simultaneously raising levels of eicosapentaenoicacid (an [n-3] fatty acid). This approach has alreadybeen successful in the treatment of rheumatoid arthritisin humans.4,77 Otherwise, the antiinflammatory effectsthat may accrue from the displacement of arachidonicacid from phospholipids by eicosapentaenoic acidcould be mitigated by an associated reduction in diho-mo--linolenic acid.72

AtherosclerosisWhether (n-3) fatty acid supplementation is effective

in the prevention or treatment of atherosclerosis in hu-mans is controversial.4 Although this disorder is not amajor concern in small animal medicine, it is interest-ing to note the potential adverse effects of (n-3) fattyacid consumption on risk factors for coronary heartdisease (namely, low-density lipoprotein [LDL] choles-terol).

In several studies, fish-oil consumption significantlyincreased LDL cholesteroleven when fed in very low,clinically practical doses.78,79 Fish oil has also adverselyaffected serum lipids to yield an atherogenic lipid pro-file in hypertensive men.80 As mentioned, eicosapen-

taenoic acid and docosahexaenoic acid (which are [n-3]fatty acids) are more subject to oxidation than is arachi-donic acid (an [n-6] fatty acid). Oxidation of the fattyacids may increase the atherogenicity of the LDL parti-cles containing them. In humans, there is growing evi-dence that lipid peroxidation, especially oxidation ofLDL cholesterol, may play a pivotal role in atherogene-sis.25 Whether dietary (n-3) fatty acids could lead to aclinically relevant increase in oxidation of LDL in vivoor whether this is prevented by added antioxidants isunknown.19 Epidemiologic and experimental data showno increase in atherosclerosis induced by (n-3) fatty

acids.21

ToleranceIn human clinical trials, dietary supplementation with

(n-3) polyunsaturated fatty acids has been well tolerat-ed. Over a 5-year period, one research group reportedthat mild gastrointestinal adverse effects had occurredbut often subsided during continued intake of (n-3) fat-ty acids.25 No bleeding episodes were reported, and noone withdrew from the trials because of adverse effects.

In a study of dogs, reported side effects of (n-3) fattyacid supplementation included lethargy, pruritus, vom-

iting, diarrhea, and urticaria (4 of 45 dogs).81 No bleed-ing episodes were reported. Two dogs were withdrawnfrom the trial because of adverse effects.

SUMMARY

Dietary supplementation with (n-3) fatty acids seemsto be well tolerated and without serious adverse effectsin humans. However, caution should always be exer-cised in extrapolating data from studies of humans orother species to dogs or cats. Nevertheless, the majorsafety issues of long-term dietary intake of (n-3) fattyacids appear to be increased lipid peroxidation, risk ofbleeding, and immunoincompetence.

At present, it seems important to recommend a highdietary intake of vitamin E to prevent the productionof harmful oxidation products and to choose dietary(n-3) fatty acid supplements that contain added antiox-

idants. The risk of bleeding seems minimal. There havebeen no reports of bleeding during human clinical trialsof fish-oil supplementation.21Whether (n-3) fatty acidscan suppress the immune system below its normal levelof competence is unknown.

Competition between fatty acids for metabolic path-ways should also be considered. Research is needed todetermine whether increased levels of dihomo--linolenic acid and eicosapentaenoic acid in the diet arenecessary to achieve optimum health for dogs and cats,as it is in the successful treatment of rheumatoid arthri-tis in humans.4,77

Long-term studies examining the beneficial effects ofdietary (n-3) fatty acid supplementation in small ani-mal patients provide an excellent opportunity to studythe possible toxic or unfavorable effects. Few studieshave focused on the adverse effects, tolerability, andsafety issues of (n-3) fatty acid administration to dogsor cats. Such safety studies are indicated before

widespread or unconditional recommendations can bemade regarding long-term supplementation with (n-3)fatty acids or alteration of the ratio of (n-3) to (n-6) fat-ty acids in the diet.

About the AuthorDr. 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).

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Potential Adverse Effects of Long-term Consumption of Fatty Acids

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